rs117187202
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):āc.4376A>Gā(p.Asn1459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 1,600,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4376A>G | p.Asn1459Ser | missense_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4376A>G | p.Asn1459Ser | missense_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.4007A>G | p.Asn1336Ser | missense_variant | 11/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.4376A>G | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000408 AC: 10AN: 245108Hom.: 0 AF XY: 0.0000301 AC XY: 4AN XY: 132772
GnomAD4 exome AF: 0.00000621 AC: 9AN: 1448118Hom.: 0 Cov.: 35 AF XY: 0.00000557 AC XY: 4AN XY: 717752
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74492
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Sep 18, 2010 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 10, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 02, 2009 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 03, 2021 | - - |
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). - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 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. - |
Invasive lobular breast carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Feb 27, 2017 | - - |
Ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Feb 27, 2017 | - - |
Breast neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2023 | Observed in individuals with breast or ovarian cancer (Suter 2004, Chao 2016, Zhong 2016, Lai 2017, Li 2017, Chen 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4604A>G; This variant is associated with the following publications: (PMID: 14973102, 28664449, 31131967, 27257965, 28222693, 27907908, 27157322, 31867841, 30702160, 31825140, 32467295, 29884841, 32377563) - |
Familial cancer of breast Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2023 | Variant summary: BRCA2 c.4376A>G (p.Asn1459Ser) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093), located between repeat 3 and 4 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 4.3e-05 in 276508 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.0006 (in the gnomAD v2.1 dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), allowing no clear conclusions about variant significance. The variant, c.4376A>G, has been reported in the literature in individuals of East Asian origin affected with breast- or ovarian cancer (Lai_2017, Bhaskaran_2019), but was also found in several unaffected East Asian controls (Lai_2017, Momozawa_2018, Dong_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 7/60466 cases, but was also found in 9/53461 controls (Dorling_2021, reported through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a large scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31131967, 28222693, 30287823, 30702160, 32467295, 33471991). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
BRCA2-related cancer predisposition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 05, 2024 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at