abstract: Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

"Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers.
The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations.
The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers.
The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p<10(-4)). In contrast, the cumulative risk of cancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives."

media: Unleashing the genome in the bottle (Ion Torrent dna testing)

MORE STILL TO LEARN

"Another challenge is that although a person's genome doesn't change, its meaning will. As scientists uncover more DNA variants that protect against disease and variants that make it more likely, a genome sequence that meant one thing in 2012 will have a different meaning in 2013, not to mention 2020.
A DNA variant that was once thought to be dangerous "might turn out to be benign if countered by another," says Greely. "Whose responsibility will it be to tell you that, years later?" DNA testing companies offer subscriptions that give customers regular updates like that."

Read more: http://www.vancouversun.com/health/Unleashing+genome+bottle/5990610/story.html#ixzz1jLlmdIDW

free full access: Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations

Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations

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Article Outline

• Positive BRCA1 or BRCA2
• Negative BRCA1 and BRCA2
• Variant of Uncertain Clinical Significance
• Case No. 1: BRCA1 VUS
  • Clinical Discussion Points
• Case No. 2: BRCA2 VUS
• Case No. 3: BRCA2 VUS Favoring Polymorphism
• Clinical Discussion Points (Cases No. 2 and 3)
• Clinical Geneticists' Opinions
• Cancer Geneticists' Opinions
• Clinical Geneticists' Opinions
• Discussion
• References
• Copyright

abstract: Familial Cancer, A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathological one

Abstract

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6 (c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were studied for mutations and identified as carriers of both variants. In spite of a relatively high mean age of cancer onset (59.5 years) in the family, many CRC patients and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present study confirms the previous findings, and suggests that MSH6 (c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family. Moreover, our results strongly support the strategy to functionally assess all identified VUS before predictive gene testing and genetic counseling are offered to a family.

LOVD - An Open Source DNA variation database system (eg. genetic testing/unknown clinicial variant/s)

LOVD stands for Leiden Open (source) Variation Database.
LOVD's purpose : To provide a flexible, freely available tool for Gene-centered collection and display of DNA variations.

Mutalyzer

LOVD features integration with the Mutalyzer sequence variant nomenclature checker, allowing for direct nomenclature checking of sequence variants during the submission process.

If you are looking for a specific gene database, please check the list of gene variant databases at the HGVS site, in our list of LSDBs, or in the list of registered LOVD installations.

Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier sta

"....The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status."

Scientists ID 5 Gene Variants Linked to Ovarian Cancer

"...The researchers analyzed the DNA of more than 10,000 women with ovarian cancer and more than 13,000 women without the disease. They found five genetic variants in regions of the genome (chromosomes 2, 3, 8, 17 and 19) associated with ovarian cancer risk.
"I think that the most important message women can take away from this work is that we are making progress in understanding ovarian cancer," Paul Pharoah, of Cancer Research UK Center for Genetic Epidemiology at Cambridge University, and senior author on two of the studies, said in the news release.....cont'd