rs149262370
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000465.4(BARD1):c.2116A>G(p.Lys706Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K706R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000465.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.2116A>G | p.Lys706Glu | missense_variant | 11/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.2116A>G | p.Lys706Glu | missense_variant | 11/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251320Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135812
GnomAD4 exome AF: 0.000155 AC: 226AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 727236
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74358
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 18, 2023 | The BARD1 c.2116A>G (p.Lys706Glu) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 9 of 60466 cases and 6 of 53461 controls (PMID: 33471991), and in a small case-control study of epithelial ovarian cancer in 2 of 3236 cases and 1 of 3431 controls (PMID: 26315354). It has been reported in other individuals with breast, colorectal, and endometrial cancer (25186627, 27443514, 29945567, 32885271). This variant is present in two individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 706 of the BARD1 protein (p.Lys706Glu). This variant is present in population databases (rs149262370, gnomAD 0.02%). This missense change has been observed in individual(s) with BARD1-related conditions (PMID: 26315354, 27443514, 29596542, 32268276, 33118316). ClinVar contains an entry for this variant (Variation ID: 127730). 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. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 15, 2023 | In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 25186627 (2015), see also LOVD (http://databases.lovd.nl/shared/genes/BARD1)), endometrial cancer (PMID: 27443514 (2016)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMID: 33118316 (2020)). The variant was also observed in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BARD1)). The frequency of this variant in the general population, 0.0002 (26/129080 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 27443514, 25230021, 29596542, 25186627, 33875564) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2016 | Variant summary: The BARD1 c.2116A>G (p.Lys706Glu) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 8/121230 control chromosomes at a frequency of 0.000066, which does not exceed the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188). It was observed in an endometrial cancer patient however, without strong evidence of causality. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 16, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 16, 2021 | - - |
Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 08, 2023 | The BARD1 c.2116A>G (p.Lys706Glu) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 9 of 60466 cases and 6 of 53461 controls (PMID: 33471991), and in a small case-control study of epithelial ovarian cancer in 2 of 3236 cases and 1 of 3431 controls (PMID: 26315354). It has been reported in other individuals with breast, colorectal, and endometrial cancer (25186627, 27443514, 29945567, 32885271). This variant is present in two individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Lys706Glu variant was identified in 3 of 7234 proband chromosomes (frequency: 0.0004) from individuals or families with epithelial ovarian cancer or endometrial carcinoma and was present in 1 of 6862 control chromosomes (frequency: 0.0002) from healthy individuals (Ramus 2015, Ring 2016). The variant was identified in dbSNP (ID: rs149262370) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and two clinical laboratories), MutDB, and in Zhejiang University databases (1x). The variant was identified in control databases in 26 of 277080 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), European in 25 of 126608 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys706 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 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at