Submissions for variant NM_000059.4(BRCA2):c.2330A>G (p.Asp777Gly)

gnomAD frequency: 0.00001  dbSNP: rs780489283

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164609	SCV000215272	likely benign	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000196448	SCV000254174	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-29	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 185230). This missense change has been observed in individual(s) with breast cancer (PMID: 21120943). This variant is present in population databases (rs780489283, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 777 of the BRCA2 protein (p.Asp777Gly).
Counsyl	RCV000409339	SCV000489712	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001721063	SCV000567766	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21120943, 31131967, 28726806)
Color Diagnostics, LLC DBA Color Health	RCV000164609	SCV000688750	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 777 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 21120943). This variant has been identified in 3/250960 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000481454	SCV001362887	uncertain significance	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2330A>G (p.Asp777Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2330A>G has been reported in the literature in at-least one individual affected with Breast Cancer (Caux-Moncoutier_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164609	SCV003848231	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353765	SCV000591800	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp777Gly variant was identified in 1 of 3050 proband chromosomes (frequency 0.0003) from individuals with breast or ovarian cancer (Caux-Moncoutier 2011). The variant was also identified in the UMD 2x as an unclassified variant, where it was reported to have co-occurred with a pathogenic BRCA1 mutation, increasing the likelihood that this variant does not have clinical significance. The p.Asp777 residue is poorly conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In addition, the p.Asp777Gly variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in all 5 different programs. However, this information is not predictive enough to rule out pathogenicity. 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 predicted benign.