rs3738888
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000465.4(BARD1):c.1972C>T(p.Arg658Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,728 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00733 AC: 1114AN: 152050Hom.: 15 Cov.: 32
GnomAD3 exomes AF: 0.00843 AC: 2118AN: 251368Hom.: 10 AF XY: 0.00785 AC XY: 1067AN XY: 135856
GnomAD4 exome AF: 0.00868 AC: 12682AN: 1461560Hom.: 54 Cov.: 30 AF XY: 0.00836 AC XY: 6077AN XY: 727102
GnomAD4 genome AF: 0.00731 AC: 1113AN: 152168Hom.: 15 Cov.: 32 AF XY: 0.00782 AC XY: 582AN XY: 74388
ClinVar
Submissions by phenotype
Familial cancer of breast Benign:6
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. -
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not specified Benign:5
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Hereditary cancer-predisposing syndrome Benign:4
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This alteration is classified as 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. -
Triple-Negative Breast Cancer Finding Uncertain:1
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not provided Benign:1
BARD1: BP4, BS1, BS2 -
Malignant tumor of breast Benign:1
The BARD1 p.Arg658Cys variant was identified in 9 of 2368 proband chromosomes (frequency: 0.004) from individuals or families with breast and/or ovarian cancer (Karppinen 2004, Klonowska 2015, Vahteristo 2006). The variant was also identified in the following databases: dbSNP (ID: rs3738888) as “With other allele”, ClinVar (6x, as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics.Inc, and as likely benign by Illumina Clinical Services, Counsyl), Clinvitae (4x, as benign and likely benign), and Zhejiang Colon Cancer Database (6x, as probably pathogenic). The variant was not identified in Cosmic nor MutDB databases. The variant was identified in control databases in 2270 (11 homozygous) of 277098 chromosomes at a frequency of 0.008 in the following populations: Finnish in 336 of 25784 chromosomes (freq. 0.013), Latino in 425 of 34414 chromosomes (freq. 0.012), East Asian in 206 of 18868 chromosomes (freq. 0.01), European in 1067 of 126610 chromosomes (freq. 0.0084), other in 53 of 6462 chromosomes (freq. 0.008), South Asian in 125 of 30782 chromosomes (freq. 0.004), and African in 58 of 2403 chromosomes (freq. 0.0024), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg658Cys residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. There are conflicting predictions in the literature regarding the clinical significance of the p.Arg658Cys variant. Some studies refer to this variant as potentially pathological (Klonowska 2015), but functional studies do not predict clinical significance for this variant although it is in a functional domain (Lee 2015). In another study this variant has been utilized as putative benign polymorphism in multiple functional assays (Sauer 2005). A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) was identified in 1 individual with breast cancer by our laboratory, increasing the likelihood that p.Arg658Cys variant does not have clinical significance. 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. -
Hereditary cancer Benign:1
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at