Submissions for variant NM_000059.4(BRCA2):c.8432A>G (p.Asp2811Gly)

gnomAD frequency: 0.00001  dbSNP: rs80359090

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045516	SCV000073529	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455611	SCV000538495	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 paper; ClinVar: 1 VUS
Color Diagnostics, LLC DBA Color Health	RCV000771458	SCV000903875	likely benign	Hereditary cancer-predisposing syndrome	2016-04-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771458	SCV001178907	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-16	criteria provided, single submitter	clinical testing	The p.D2811G variant (also known as c.8432A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8432. The aspartic acid at codon 2811 is replaced by glycine, an amino acid with similar properties. This alteration was reported in a woman with breast cancer from a population based case-control study (Malone KE et al. Cancer 2000 Mar; 88(6):1393-402). Of note, this alteration is also known as 8660A>G in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284112	SCV001469725	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455611	SCV002555958	uncertain significance	not specified	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8432A>G (p.Asp2811Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8432A>G has been reported in the literature in an individual affected with early onset breast cancer (Malone_2000). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications have used a variety of in silico modelling tools to predict the impact of the variant on protein function and have classified it as having a neutral or likely benign effect (e.g. Karchin_2008, Padilla_2019, Cline_2019). For example, 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). This classification was also supported by consensus from six prediction teams in a second publication, also as part of the CAGI5 ENIGMA Challenge (Cline_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely benign and three as VUS. . Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113931	SCV000147362	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing