Submissions for variant NM_000465.4(BARD1):c.1127C>T (p.Ser376Leu)

gnomAD frequency: 0.00009  dbSNP: rs587782333

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131256	SCV000186219	likely benign	Hereditary cancer-predisposing syndrome	2018-11-29	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	RCV000199235	SCV000254565	uncertain significance	Familial cancer of breast	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 376 of the BARD1 protein (p.Ser376Leu). This variant is present in population databases (rs587782333, gnomAD 0.02%). This missense change has been observed in individual(s) with hereditary cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 142247). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine 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.
GeneDx	RCV000236301	SCV000293589	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing multigene testing for hereditary cancer, as well as both cases and controls in a breast cancer study, and absent in cases but present in controls in an ovarian cancer study (Ramus et al., 2015; Tsaousis et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26315354, 33471991, 30541756, 31159747, 36187937)
GeneKor MSA	RCV000131256	SCV000821886	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131256	SCV000902834	likely benign	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251335	SCV001426897	uncertain significance	not specified	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1127C>T (p.Ser376Leu) 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. The variant allele was found at a frequency of 6.4e-05 in 251330 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than predicted for a pathogenic variant in BARD1 causing Breast Cancer (6.4e-05 vs 0.00025), allowing no conclusion about variant significance. c.1127C>T has been reported in the literature in individuals who underwent genetic testing for familial cancers (e.g. Tsaousis_2019), but also in healthy controls (e.g. Ramus_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=2) . Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000131256	SCV002526984	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000199235	SCV002580148	uncertain significance	Familial cancer of breast	2022-06-07	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV005251077	SCV005903095	likely benign	Hereditary breast ovarian cancer syndrome	2025-04-02	criteria provided, single submitter	curation	According to the ACMG SVI adaptation criteria we chose these criteria: BP1 (supporting benign): missense variants =VUS in HGMD/ClinVar; Missense 447 observed/415 expected: o/e = 1.08, BP4 (supporting benign): REVEL = 0.082 (as per Pejaver (2022, PMID: 36413997))
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359256	SCV005918999	uncertain significance	BARD1-related cancer predisposition	2019-12-11	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000199235	SCV004228576	not provided	Familial cancer of breast		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-30-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.