Submissions for variant NM_000465.4(BARD1):c.764A>G (p.Asn255Ser)

gnomAD frequency: 0.00009  dbSNP: rs138904906

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236599	SCV000293074	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31871109, 23056176, 32039725, 32885271, 32832836, 32866190)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529895	SCV000633064	uncertain significance	Familial cancer of breast	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 255 of the BARD1 protein (p.Asn255Ser). This variant is present in population databases (rs138904906, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 32039725, 32866190, 32885271). ClinVar contains an entry for this variant (Variation ID: 245891). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000573274	SCV000660803	likely benign	Hereditary cancer-predisposing syndrome	2024-04-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000573274	SCV000682813	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 255 of the BARD1 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 identified in two individuals affected with breast cancer in the literature (PMID: 31871109, 32039725). This variant has been identified in 8/253060 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.
Counsyl	RCV000529895	SCV000786352	uncertain significance	Familial cancer of breast	2018-04-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780946	SCV000918621	uncertain significance	not specified	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.764A>G (p.Asn255Ser) 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 2.7e-05 in 221662 control chromosomes, predominantly at a frequency of 0.00038 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.764A>G has been reported in the literature in individuals affected with breast cancer without strong evidence of causality (Adedokun_2020, Bishop_2020, Carvalho_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23056176, 32039725, 31871109, 32866190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236599	SCV001469363	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225531	SCV002505132	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000529895	SCV004019275	uncertain significance	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000529895	SCV004214949	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000529895	SCV005655840	uncertain significance	Familial cancer of breast	2024-03-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357269	SCV001552688	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Asn255Ser variant was not identified in the literature. The variant was identified in dbSNP (rs138904906) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 5 others). The variant was identified in control databases in 8 of 247,792 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23,516 chromosomes (freq: 0.0003), but not in the “Other”, Latino, European, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Asn255 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. This variant is classified as a variant of uncertain significance.