Submissions for variant NM_000059.4(BRCA2):c.1762A>G (p.Asn588Asp)

gnomAD frequency: 0.00004  dbSNP: rs398122731

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703984	SCV000210567	likely benign	not provided	2019-05-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 18824701, 27376475, 26898890)
Ambry Genetics	RCV000163030	SCV000213518	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000077665	SCV000488195	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531905	SCV000635175	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163030	SCV000683443	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077665	SCV001266759	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001109420	SCV001266760	uncertain significance	Fanconi anemia complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160207	SCV001821461	likely benign	not specified	2021-08-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1762A>G (p.Asn588Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249790 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1762A>G has been reported in the literature in individuals affected with breast/ovarian and prostate cancer (example, Lu_2012, Kote-Jari_2011, Spearman_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally, multifactorial probability models support a "likely not pathogenic" (IARC class 2) outcome (Lindor_2012). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high-throughput functional evaluation utilizing BRCA2-deficient cells and poly (ADP ribose) polymerase (PARP) inhibitors (example, Ikegami_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as likely benign (n=5). Based on the evidence outlined above, the variant was re-classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000160207	SCV002068445	likely benign	not specified	2018-03-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000531905	SCV002819167	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-05-11	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163030	SCV003851618	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703984	SCV004219519	likely benign	not provided	2023-03-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703984	SCV004562453	likely benign	not provided	2023-08-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001703984	SCV004848655	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	The p.Asn588Arg variant in BRCA2 has been reported in at least 5 individuals with BRCA2-associated cancers (Spearman 2008 PMID: 18824701, Kote-Jarai 2011 PMID: 21952622, Lu 2012 PMID: 22476429, Schenkel 2016 PMID: 27376475, Caminsky 2016 PMID: 26898890). It has also been identified in 0.005% (6/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 91757). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In silico functional studies provide some evidence that this variant does not impact protein function (Ikegami 2020 PMID: 32444794); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.
Sharing Clinical Reports Project (SCRP)	RCV000077665	SCV000109468	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353480	SCV000591764	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn588Asp variant was identified in 2 of 3932 proband chromosomes (frequency: 0.0005) from individuals or families with breast and prostate cancer (Spearman 2008, Kote-Jarai 2011). The variant was identified in dbSNP (rs398122731) as “with likely benign allele”, ClinVar (classified as likely benign by Invitae, Color, GeneDx, Ambry Genetics, and three other submitters), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 7 of 281,182 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 6 of 128,542 chromosomes (freq: 0.00005) and African in 1 of 24,676 chromosomes (freq: 0.00004), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The variant was identified by our laboratory as co-occurring with a pathogenic BRCA1 variant (c.5194-2A>G, p.?). The p.Asn588 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.