chr2-214781152-G-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000465.4(BARD1):āc.722C>Gā(p.Ser241Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000603 in 1,576,586 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S241P) 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 -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BARD1 | NM_000465.4 | c.722C>G | p.Ser241Cys | missense_variant | 4/11 | ENST00000260947.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BARD1 | ENST00000260947.9 | c.722C>G | p.Ser241Cys | missense_variant | 4/11 | 1 | NM_000465.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000269 AC: 41AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000134 AC: 29AN: 216258Hom.: 0 AF XY: 0.000112 AC XY: 13AN XY: 116504
GnomAD4 exome AF: 0.000639 AC: 910AN: 1424296Hom.: 19 Cov.: 34 AF XY: 0.000627 AC XY: 443AN XY: 706110
GnomAD4 genome AF: 0.000269 AC: 41AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74468
ClinVar
Submissions by phenotype
Familial cancer of breast Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jun 27, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 24, 2023 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2017 | Variant summary: The BARD1 c.722C>G (p.Ser241Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of ExAC in 25/114604 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002784 (24/8622). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. A case-control study found this variant to not be significantly associated with breast cancer (Ishitobi_BARD1_2003). This variant was found in a pancreatic ductal adenocarcinoma patient with no strong evidence for causality (Ohmoto_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2014 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 27, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 12, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2015 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 14, 2015 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 11, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 05, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BARD1 p.Ser241Cys variant was identified in 11 of 286 proband chromosomes (frequency: 0.04) from individuals or families with breast cancer and was present in 8 of 310 control chromosomes (frequency: 0.03) from healthy individuals (Ishitobi 2003). The variant was also identified in the following databases: dbSNP (ID: rs3738885) as With Uncertain significance, other allele, ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics; classified as likely benign by Counsyl, QDNISJC clinical laboratory), Clinvitae, MutDB, Zhejiang Colon Cancer Database (2X). The variant was not identified in Cosmic, database. The variant was identified in control databases in 27 of 211500 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 4468 chromosomes (freq: 0.0002), East Asian in 26 of 15562 chromosomes (freq: 0.002); it was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. Although the p.Ser241 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at