Submissions for variant NM_000465.4(BARD1):c.1586G>A (p.Arg529Gln)

gnomAD frequency: 0.00006  dbSNP: rs753479021

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167371	SCV000218224	likely benign	Hereditary cancer-predisposing syndrome	2022-12-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226041	SCV000284921	likely benign	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000485842	SCV000568128	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast, ovarian, or colon cancer, and also in unaffected controls (Young et al., 2016; Yurgelun et al., 2017; Kwong et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25922291, 26787654, 28135145, 33471991, 32068069, 18480049, 31371347)
Color Diagnostics, LLC DBA Color Health	RCV000167371	SCV000682714	likely benign	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000226041	SCV000786325	uncertain significance	Familial cancer of breast	2018-04-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485842	SCV001153290	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BARD1: PP3, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582659	SCV001821420	likely benign	not specified	2021-08-29	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1586G>A (p.Arg529Gln) 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 0.00014 in 251276 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1586G>A has been reported in the literature as a VUS in settings of multigene cancer panel testing among affected individuals (example, Yurgelun_2017, Kwong_2020). These report(s) 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000167371	SCV002527026	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000226041	SCV004019242	likely benign	Familial cancer of breast	2023-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000485842	SCV004225979	uncertain significance	not provided	2023-01-16	criteria provided, single submitter	clinical testing	PP3
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357502	SCV001552988	uncertain significance	Familial pancreatic carcinoma		no assertion criteria provided	clinical testing	The BARD1 p.Arg529Gln variant was identified in 1 of 2116 proband chromosomes (frequency: 0.0005) from individuals or families with colorectal cancer (Yurgelun 2017) and was also identified in a study which included 1297 breast cancer cases and 1121 controls, however the frequency of this variant was not specified (Young 2016). The variant was also identified in dbSNP (ID: rs753479021) as "With Uncertain significance allele", and in ClinVar and Clinvitae (classified as likely benign by Invitae and as uncertain significance by Ambry Genetics, GeneDx, Color and Counsyl). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 37 of 276996 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 3 of 126562 chromosomes (freq: 0.00002), East Asian in 34 of 18864 chromosomes (freq: 0.002); it was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The variant was observed in the Exome Aggregation Consortium database (August 8th 2016) in the East Asian population in 19 of 8650 chromosomes (freq: 0.002) including 1 homozygous individual. The p.Arg529 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.