Submissions for variant NM_000465.4(BARD1):c.1148T>A (p.Met383Lys)

gnomAD frequency: 0.00003  dbSNP: rs763596413

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164393	SCV000215029	likely benign	Hereditary cancer-predisposing syndrome	2024-01-11	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.
Invitae	RCV000462462	SCV000545603	uncertain significance	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 383 of the BARD1 protein (p.Met383Lys). This variant is present in population databases (rs763596413, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 32959997). ClinVar contains an entry for this variant (Variation ID: 185039). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507431	SCV000600172	uncertain significance	not specified	2017-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164393	SCV000682671	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with lysine at codon 383 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 reported in individuals affected with breast cancer (PMID: 32959997, 35402282). This variant has been identified in 2/282650 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.
GeneDx	RCV001569258	SCV001793298	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Adedokun et al., 2020; Uyisenga et al., 2020); This variant is associated with the following publications: (PMID: 32959997, 31871109)
Fulgent Genetics, Fulgent Genetics	RCV000462462	SCV002780800	uncertain significance	Familial cancer of breast	2021-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354646	SCV001549311	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The BARD1 p.Met383Lys variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang University databases. The variant was identified in dbSNP (ID: rs763596413) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, and one other clinical laboratory). The variant was identified in control databases in 2 of 276950 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017), specifically in the African population in 2 of 24030 chromosomes (freq: 0.000083), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Met383 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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.