Submissions for variant NM_000465.4(BARD1):c.651A>G (p.Lys217=)

gnomAD frequency: 0.00001  dbSNP: rs768866006

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166523	SCV000217323	likely benign	Hereditary cancer-predisposing syndrome	2014-10-27	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	RCV001355852	SCV000512239	likely benign	not provided	2019-04-10	criteria provided, single submitter	clinical testing
Invitae	RCV000477170	SCV000557492	likely benign	Familial cancer of breast	2023-12-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166523	SCV000682808	likely benign	Hereditary cancer-predisposing syndrome	2016-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166523	SCV002529638	likely benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003895153	SCV004709191	likely benign	BARD1-related disorder	2024-01-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355852	SCV001550857	likely benign	not provided		no assertion criteria provided	clinical testing	The BARD1 p.Lys217= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs768866006) as “With Likely benign allele”, and ClinVar (4x as likely benign by Ambry Genetics, GeneDx, Invitae, Color). The variant was identified in control databases in 6 of 258076 chromosomes (1 homozygous) at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 29740 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 120988 chromosomes (freq: 0.000008), East Asian in 2 of 17562 chromosomes (freq: 0.0001), and South Asian in 2 of 26010 chromosomes (freq: 0.00008). While the variant was not observed in the African, Other, Ashkenazi Jewish or Finnish populations. The p.Lys217= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.