BRCA2 NM_000059.3:c.7759C>T, Leu2587Phe

Variant summary: BRCA2 c.7759C>T (p.Leu2587Phe) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251514 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.7759C>T has been reported in the literature in individuals undergoing evaluation for breast/colorectal cancer (e.g. Velasco_2005, Garre_2014, Tsai_2019). Some of these reports classify the variant as a VUS within settings of multigene panel testing (e.g. Tsai_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported in the LOVD database (BRCA1 c.2197_2201delGAGAA, p.Glu733fsX5). At least two publications report experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Richardson_2021, Hu_2022). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29849630, 27165003, 29881398, 24814045, 29394989, 29884841, 35736817, 16758124, 20167696, 33609447, 30374176, 15937982, 30055349). ClinVar contains an entry for this variant (Variation ID: 141335). Based on the evidence outlined above, the variant was classified as likely benign.

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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.