rs138904906
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000465.4(BARD1):c.764A>G(p.Asn255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,582,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. N255D) 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.764A>G | p.Asn255Ser | missense_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.764A>G | p.Asn255Ser | missense_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000271 AC: 6AN: 221662Hom.: 0 AF XY: 0.0000168 AC XY: 2AN XY: 119138
GnomAD4 exome AF: 0.0000154 AC: 22AN: 1429728Hom.: 0 Cov.: 34 AF XY: 0.00000988 AC XY: 7AN XY: 708562
GnomAD4 genome ? AF: 0.0000919 AC: 14AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74480
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 255 of the BARD1 protein (p.Asn255Ser). This variant is present in population databases (rs138904906, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 32039725, 32866190). ClinVar contains an entry for this variant (Variation ID: 245891). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31871109, 23056176, 32039725, 32885271, 32832836) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2022 | The frequency of this variant in the general population, 0.00033 (8/24392 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, it has been reported in women affected with breast cancer (PMID: 31871109 (2019), 32039725 (2020), 32885271 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2022 | This missense variant replaces asparagine with serine at codon 255 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 identified in two individuals affected with breast cancer in the literature (PMID: 31871109, 32039725). This variant has been identified in 8/253060 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2024 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2023 | Variant summary: BARD1 c.764A>G (p.Asn255Ser) results in a 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 2.7e-05 in 221662 control chromosomes, predominantly at a frequency of 0.00038 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.764A>G has been reported in the literature in individuals affected with breast cancer without strong evidence of causality (Adedokun_2020, Bishop_2020, Carvalho_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23056176, 32039725, 31871109, 32866190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as 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.Asn255Ser variant was not identified in the literature. The variant was identified in dbSNP (rs138904906) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 5 others). The variant was identified in control databases in 8 of 247,792 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23,516 chromosomes (freq: 0.0003), but not in the “Other”, Latino, European, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Asn255 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at