It's not known among some healthcare consumers that there are a host of BRCA variants other than the standard ones. Normal BRCA testing looks for three specific genetic variants that are linked to hereditary cancers. Two of these variants — 185delAG and 5382insC — are in the BRCA1 gene. One variant — called 6174delT — is in the BRCA2 gene. A patient may test positive for a variant other than these common ones and it may not be clear under such circumstances what treatment to offer to the patient. The BRCA Exchange is now available on the web that may be of assistance to researchers, physicians, and patients in understanding these variants (see: BRCA Exchange aggregates data on thousands of BRCA variants to inform understanding of cancer risk), Below is an excerpt from the article about this new web reference site:
A global resource that includes data on thousands of inherited variants in the BRCA1 and BRCA2 genes is available to the public. The BRCA Exchange was created through the BRCA Challenge, a long-term demonstration project initiated by the Global Alliance for Genomics and Health (GA4GH) to enhance sharing of BRCA1 and BRCA2 data. The resource, available through a website and a new smartphone app, allows clinicians to review expert classifications of variants in these major cancer predisposition genes as part of their individual assessment of complex questions related to cancer prevention, screening, and intervention for high-risk patients....Certain inherited variants in these genes can increase the risk of breast, ovarian, and other cancers by varying degrees, whereas others are not associated with disease. Clinicians and patients need to know whether a given variant is likely to be disease-associated (pathogenic) and how likely a pathogenic variant is to cause cancer (penetrance). Until now, the available data on the inherited variants in these genes were not aggregated in a comprehensive way. The BRCA Exchange dataset is composed of information from existing clinical databases—the Breast Cancer Information Core, ClinVar, and the Leiden Open Variation Database—as well as population databases and data from clinicians, clinical laboratories, and researchers worldwide. It currently includes more than 20,000 unique BRCA1 and BRCA2 variants.
Here's a quote from an article about BRCA mutations seen in Norwegian patients (see: BRCA1 and BRCA2 mutation spectrum – an update on mutation distribution in a large cancer genetics clinic in Norway):
The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.
The takeaway message here is that BRCA testing for a patient may not be straightforward if the mutation discovered is not one of the common ones (i.e. a VUS -- variant of unknown significance). However, research is being conducted to understand and clinical significance of these variations when they occur (see: What’s a “Variant of Uncertain Significance?” A VUS?).
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