Submissions for variant NM_000059.4(BRCA2):c.322A>C (p.Asn108His)

gnomAD frequency: 0.00034  dbSNP: rs80358567

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113415	SCV001161579	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00136 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae	RCV001079112	SCV000072166	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131576	SCV000186584	likely benign	Hereditary cancer-predisposing syndrome	2020-05-13	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.
GeneDx	RCV000590284	SCV000210232	likely benign	not provided	2020-08-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12491487, 11030417, 23231788, 12955716, 16234499, 9971877, 22476429, 26580448)
Eurofins Ntd Llc (ga)	RCV000590284	SCV000230001	uncertain significance	not provided	2014-11-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000113415	SCV000488864	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000168534	SCV000600542	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168534	SCV000694681	benign	not specified	2021-10-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.322A>C (p.Asn108His) 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 variant allele was found at a frequency of 7.2e-05 in 251048 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.322A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Wagner_1999, Gao_2000, Diez_2003, Nanda_2005, Lu_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrences with pathogenic variants have been observed via internal testing [BRCA1 c.3748G>T, p.Glu1250X; BRCA1 c.(4185+1_4186-1)_(4357+1_4358-1)dup], providing supporting evidence for a benign role. Nine submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Five ClinVar submitters have cited the variant as likely benign, 2 submitters have cited it as variant of unknown significance and 2 submitters (including an expert panel, ENIGMA) have cited is as benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000131576	SCV000903028	likely benign	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000113415	SCV001138953	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-27	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001079112	SCV002025837	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001079112	SCV002515244	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131576	SCV002533774	likely benign	Hereditary cancer-predisposing syndrome	2020-11-02	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003415790	SCV004114961	uncertain significance	BRCA2-related condition	2022-11-04	criteria provided, single submitter	clinical testing	The BRCA2 c.322A>C variant is predicted to result in the amino acid substitution p.Asn108His. This variant has been reported in multiple individuals with breast and/or ovarian cancer (Wagner et al. 1999. PubMed ID: 9971877, Gao et al. 2000. PubMed ID: 11030417, Díez et al. 2003. PubMed ID: 12955716, Nanda et al. 2005. PubMed ID: 16234499, Lu et al. 2012. PubMed ID: 22476429); however, no evidence was provided to support its pathogenicity. This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32899218-A-C) and has interpretations in ClinVar ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/51428/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113415	SCV000146588	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing