rs80358782
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):c.5612G>A(p.Ser1871Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1871S) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5612G>A | p.Ser1871Asn | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5612G>A | p.Ser1871Asn | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000324 AC: 8AN: 247218Hom.: 0 AF XY: 0.0000299 AC XY: 4AN XY: 133622
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1458302Hom.: 0 Cov.: 44 AF XY: 0.0000165 AC XY: 12AN XY: 725210
GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74458
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 22, 2008 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 22, 2022 | ACMG classification criteria: PM2 supporting, BP4 supporting - |
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 24, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 27, 2017 | The BRCA2 c.5612G>A; p.Ser1871Asn variant (rs80358782) has been reported in individuals with early-onset prostate cancer or breast cancer (Edwards 2003, El Saghir 2015, Lee 2008). This variant is reported multiple times in ClinVar as uncertain (Variation ID: 51891), and observed in general population databases with overall allele frequencies of 0.02 percent (1/5008 alleles, 1000 Genomes Project), and 0.006 percent (17/273156 alleles, Genome Aggregation Database). The serine at codon 1871 is weakly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, due to the limited information regarding p.Ser1871Asn, its clinical significance in uncertain at this time. REFERENCES Link to ClinVar database for p.Ser1871Asn: https://www.ncbi.nlm.nih.gov/clinvar/variation/51891/ Edwards SM et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003 Jan;72(1):1-12. El Saghir NS et al. BRCA1 and BRCA2 mutations in ethnic Lebanese Arab women with high hereditary risk breast cancer. Oncologist. 2015 Apr;20(4):357-64. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 06, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | Observed in individuals with breast or prostate cancer (Edwards et al., 2003; Lee et al., 2008; El Saghir et al., 2015; Matta et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5840G>A; This variant is associated with the following publications: (PMID: 12474142, 25777348, 18284688, 10923033, 29884841, 35264596, 31853058, 31911673, 32377563, 33471991, 36329109) - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 06, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 06, 2022 | DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.5612G>A, in exon 11 that results in an amino acid change, p.Ser1871Asn. This sequence change has been described in the gnomAD database with a frequency of 0.069% in the African/African American subpopulation (dbSNP rs80358782). The p.Ser1871Asn change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ser1871Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in individuals with BRCA2-related cancers, as well as in individuals with no history of cancer (PMID: 12474142, 25777348, 18284688, 33471991, FLOSSIES database https://whi.color.com/variant/13-32914104-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser1871Asn change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2024 | Variant summary: BRCA2 c.5612G>A (p.Ser1871Asn) results in a conservative amino acid change located in the BRCA2 repeat; IPR002093 of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 1610562 control chromosomes, predominantly at a frequency of 0.00057 within the African or African-American subpopulation in the gnomAD database (v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer (Edwards_2003, Lee_2008, El Saghir_2015, Dorling_2021) as well as in individuals without Breast And Ovarian Cancer (FLOSSIES database, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported ( BRCA1 c.798_799delTT, p.Ser267LysfsX19), providing supporting evidence for a benign role. 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: 12474142, 18284688, 25777348, 33471991). ClinVar contains an entry for this variant (Variation ID: 51891). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at