Submissions for variant NM_000059.3(BRCA2):c.2488A>G (p.Asn830Asp) (rs574039421)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132391	SCV000187483	uncertain significance	Hereditary cancer-predisposing syndrome	2017-06-02	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae	RCV000168262	SCV000218933	uncertain significance	Hereditary breast and ovarian cancer syndrome	2014-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with aspartic acid at codon 830 of the BRCA2 protein (p.Asn830Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This sequence change has not been published in the literature and is present in population databases (no rsID, 0.07%). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000222546	SCV000278840	likely benign	not specified	2018-03-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color	RCV000132391	SCV000683487	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000662824	SCV000785667	uncertain significance	Breast-ovarian cancer, familial 2	2017-10-25	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000222546	SCV000918903	likely benign	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2488A>G (p.Asn830Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.2488A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Rajkumar_2015, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.7007G>A, p.Arg2336His (internally scored as a Pathogenic)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant with conflicting classifications, "uncertain significance" (2x) and "likely benign" (1x). Based on the evidence outlined above, the variant was classified as likely benign.