Submissions for variant NM_000059.4(BRCA2):c.467A>G (p.Asp156Gly)

gnomAD frequency: 0.00022  dbSNP: rs68071147

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167806	SCV000072481	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129132	SCV000183850	likely benign	Hereditary cancer-predisposing syndrome	2018-05-18	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.
GeneDx	RCV001281728	SCV000210243	likely benign	not provided	2020-08-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21520273, 22505045, 20215541, 20104584, 14973102, 23893897, 20167696, 26941049, 16683254, 23348723, 30883759, 31131967, 31825140)
Pathway Genomics	RCV000077333	SCV000223762	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167806	SCV000267841	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000044468	SCV000588067	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281728	SCV000600601	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer or at high risk for breast and/or ovarian cancer (PMIDs: 14973102 (2004), 20104584 (2010), 26941049 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)) and prostate cancer (PMID: 36898365 (2023)). Experimental studies suggest that this variant may generate a cryptic splice donor site, resulting in an in-frame deletion of three amino acids (PMIDs: 22505045 (2012), 20215541 (2010), 30233647 (2018), and 30883759 (2019)). An additional functional study determined this variant results in normal function when cells are treated with PARP inhibitors, however, the effect of this variant on the full spectrum of BRCA2 protein function was not investigated (PMID: 32444794 (2020)). The frequency of this variant in the general population, 0.00056 (14/24866 chromosomes in African/African American subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044468	SCV000694795	uncertain significance	not specified	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.467A>G (p.Asp156Gly) results in a non-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. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5' donor site. These predictions were confirmed by studies demonstrating that the variant results in a 9 nucleotides deletion (r.467_475del) in the majority of the transcripts, which would result in an in-frame deletion of 3 amino acids (p.D156_S158del) at the protein level (Houdayer_2012, Sanz_2010, Fraile-Bethencourt_2019). The variant allele was found at a frequency of 7.2e-05 in 251690 control chromosomes, predominantly at a frequency of 0.00056 within the African or African-American subpopulation in the gnomAD database. This frequency is slightly lower than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer, therefore these data do not allow clear conclusions about the variant. c.467A>G, has been reported in the literature in at least 3 individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer (Suter_2004, Borg_2010, Houdayer_2012), though it was also found in 2 women, older than age 70 years, who have never had cancer (in FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. An in vitro study examining the effect of this variant at the protein level using an (intronless) cDNA construct, demonstrated that the Asp156Gly missense variant does not affect the HDR function of BRCA2 in a PARP-inhibitor sensitivity assay (Ikegami_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31825140, 20104584, 21520273, 30883759, 22505045, 32444794, 20215541, 14973102). ClinVar contains an entry for this variant (Variation ID: 51694). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000129132	SCV000903073	likely benign	Hereditary cancer-predisposing syndrome	2022-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000077333	SCV001138962	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000044468	SCV001157833	uncertain significance	not specified	2018-08-27	criteria provided, single submitter	clinical testing	The BRCA2 c.467A>G; p.Asp156Gly variant (rs68071147) is reported in the literature in several individuals affected with breast and/or ovarian cancer (Capanu 2011, Sanz 2010, Suter 2004). This variant is reported in ClinVar (Variation ID: 51694) and is found in the African population with an overall allele frequency of 0.05% (13/24012 alleles) in the Genome Aggregation Database. The aspartate at codon 156 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Analyses of splicing (Alamut v.2.11) predict that this variant creates a novel cryptic splice donor site, and mRNA studies indicate that splicing occurs at this cryptic site, resulting in an in-frame deletion of 9 nucleotides at the end of exon 5 (Houdayer 2012, Sanz 2010). However, due to limited information on the clinical impact of the p.Asp156Gly variant, its significance is uncertain at this time. References: Capanu M et al. Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol. 2011 Jul;35(5):389-97. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. Suter NM et al. BRCA1 and BRCA2 mutations in women from Shanghai China. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):181-9.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167806	SCV002025870	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000044468	SCV002065496	uncertain significance	not specified	2017-11-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077333	SCV000109130	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-07-09	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077333	SCV000146918	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044468	SCV000587549	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001281728	SCV001954936	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001281728	SCV001973080	uncertain significance	not provided		no assertion criteria provided	clinical testing