rs80359129
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_000059.4(BRCA2):c.8702G>A(p.Gly2901Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2901V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8702G>A | p.Gly2901Asp | missense_variant | 21/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8702G>A | p.Gly2901Asp | missense_variant | 21/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251324Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135838
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727230
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74468
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:3
Uncertain significance, flagged submission | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jun 12, 2000 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Nov 25, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 22, 2010 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 07, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 02, 2016 | Variant summary: The c.8702G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Asp. 4/4 in-silico tools predict damaging outcome for this variant. This variant is found in 14/121646 control chromosomes from ExAC at a frequency of 0.0001151. It was predominantly reported in East Asian subpopulation with an allele frequency of 0.0016 which is about 2.15 times higher than the maximum expected allele frequency of a pathogenic variant in this gene suggesting that it is likely to be a polymorphism in East Asians. The variant has been reported in several breast and/or ovarian cancer patients/families, mainly of East Asian origin, without strong evidence for pathogenicity. In one patient with thyroid and breast cancer, a truncating mutation PTEN c. 590delA was also found, possibly suggesting for an alternative disease mechanism. In addition, it was also found in once in each of benign breast cancer patient and healthy control cohorts, possibly suggesting a benign outcome. Functional studies (HDR, cell viability and drug sensitivity assays) shows neutral outcome for this variant. Three out of five clinical labs have also classified this variant as likely benign/benign (other two as uncertain significance). Taken together, this variant has currently been classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | This variant is associated with the following publications: (PMID: 26757417, 23108138, 19043619, 28277317, 14973102, 18607349, 9579822, 24323938, 22486713, 18627636, 18779604, 26221963, 11251181, 28222693, 29394989, 26848529, 29681614, 24817641, 31131967, 29884841, 31825140) - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2019 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2016 | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 02, 2019 | - - |
BRCA2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Familial cancer of breast Benign:1
Likely benign, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at