rs11571653
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000059.4(BRCA2):c.2350A>G(p.Met784Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,048 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M784I) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 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 |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.2350A>G | p.Met784Val | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2350A>G | p.Met784Val | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000611 AC: 93AN: 152216Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.000227 AC: 57AN: 250828Hom.: 2 AF XY: 0.000184 AC XY: 25AN XY: 135660
GnomAD4 exome AF: 0.00144 AC: 2098AN: 1461714Hom.: 113 Cov.: 33 AF XY: 0.00138 AC XY: 1005AN XY: 727162
GnomAD4 genome ? AF: 0.000611 AC: 93AN: 152334Hom.: 4 Cov.: 32 AF XY: 0.000671 AC XY: 50AN XY: 74504
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:6
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 10, 2011 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Oct 16, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02797 (Asian), derived from 1000 genomes (2012-04-30). - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not specified Benign:4Other:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 12, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2013 | 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: Ben by expert panel - |
not provided Benign:4
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 13, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2014 | 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. - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 15, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 29, 2015 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | - | - - |
Fanconi anemia complementation group D1 Benign:1
Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Met784Val variant has been reported in the literature in 160/11460 proband chromosomes of individuals with HBOC and sporadic breast cancer. It was also found in 35/5936 control chromosomes tested, increasing the likelihood this variant does not have clinical significance (Spearman 2008, Wagner 1999, Capanu 2011, Freedman_2004, Ishitobi_2003, Johnston_2012, Krupa_2009, Seo_2004, Han_2006). The variant has also been reported in the UMD (x1), LOVD (x2), BIC (x47), and BOCs databases. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs11571653) with a MAF score of 0.007 (1000 Genomes). Of particular interest are the findings that this variant is considered a polymorphism in the Japanese population, and that of the 168 chromosomes tested in the HapMap Japanese cohort, the variant was found in almost 20 chromosomes (allele frequency of 0.107). The p.Met784 residue is not conserved in mammals, and the variant amino acid Valine (Val) is present in the dog, rat and opossum at this position, increasing the likelihood that an alteration to this residue may not have functional significance. The identification of this variant in the presence of a second pathogenic variant increases the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as Benign. - |
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