rs80358978
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The NM_000059.4(BRCA2):c.7522G>A(p.Gly2508Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2508D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7522G>A | p.Gly2508Ser | missense_variant | 15/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7522G>A | p.Gly2508Ser | missense_variant | 15/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251392Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135868
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727244
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74370
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:2Other:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 08, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2022 | Variant summary: BRCA2 c.7522G>A (p.Gly2508Ser) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 310330 control chromosomes, predominantly at a frequency of 0.0023 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.7522G>A, has been reported in the literature in numerous individuals affected with tumors that belong to the HBOC spectrum, however it was also found in several healthy controls. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8340_8343delTAAC (p.Asn2781ValfsX39) in the BIC database and BRCA1 c.3627dupA (p.Glu1210Argfs) in Lim_2009), providing supporting evidence for a benign role. A large case-control study involving breast cancer patients and controls of Asian ancestry (Han_2017), found an enrichment of this variant in cases (OR: 3.02 (95%CI: 1.69-5.39), p-value: 0.000123). However, an other case-control association study, involving breast cancer patients and controls of Japanese ancestry (Momozawa_2018), did not demonstrate significant increase in breast/ovarian cancer risk (i.e. the variant was identified in 5/7051 female cases, and 6/11241 female controls; OR: 1.3 (95%CI: 0.3-5.2)). A further study, involving Korean breast cancer patients, where multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology), predicted this variant to be likely pathogenic, although the variant was interpreted as likely benign when applying the ACMG/AMP guidelines (Lee_2018). Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated a mild impact on BRCA2 function, representing an activity comparable to wild-type, or a somewhat hypomorphic allele (e.g. Shimelis_2017, Mesman_2018, Guidugli_2018, Ikegami_2020). Eleven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6, likely benign, n=3 or benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 06, 2016 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2022 | The c.7522G>A (p.G2508S) alteration is located in exon 15 (coding exon 14) of the BRCA2 gene. This alteration results from a G to A substitution at nucleotide position 7522, causing the glycine (G) at amino acid position 2508 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 05, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 07, 2008 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Ovarian cancer Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Jul 21, 2017 | - - |
Likely pathogenic, flagged submission | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Infiltrating duct carcinoma of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Jul 21, 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 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2, p.Gly2508Ser variant was identified in 6 of 1220 proband chromosomes (frequency: 0.005) from individuals or families with breast, ovarian and thyroid cancers. (Lim 2009, Yu 2015, Wong 2016). The variant was also identified 1x in a study of 681 health controls in an east Asian individual (Bodian 2014). The variant was also identified in dbSNP (ID: rs80358978) “With other allele.” This variant was identified in the Exome Aggregation Consortium (ExAC) database (March 14, 2016) in 13 of 8636 chromosomes (frequency: 0 0.0015) in the East Asian population, and was not found in populations of South Asians, European (Non-Finnish), African, Latino, European (Finnish) and other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In the Clinvar Database the variant was identified with conflicting interpretations: as likely benign by Invitae, GeneDX and Sharing Reports Project derived from Myriad reports, as uncertain significance by Ambry Genetics and BIC,classification was not provided by ITMI. In BIC the variant was identified 4x with unknown clinical significance. In the Fanconi Anaemia Mutation Database (LOVD) the variant was identified 2x (1x as neutral by Karchin 2008 and 1x as deleterious by Pettigrew 2008). This variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), COSMIC, GeneInsight COGR, or ARUP Laboratories Databases. The p.Gly2508 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ser (Serine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Karchin et al 2008 has concluded the variant as predicted neutral using protein likelihood ratios to determine all variants of undetermined significance in the C-terminal binding domain of the BRCA2 protein. However, the variant was predicted to result in an increased exonic splice enhancer (ESE) motif score at an evolutionarily conserved ESE (Pettigrew 2008) and therefore the variant was concluded to be deleterious. In a multigene panel study of breast cancer predisposition in Asians, the authors categorized the p.Gly2508Ser variant as pathogenic using Manchester and Boadicea scores. Family history was evaluated in this multigene study (Wong 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Cancer of the pancreas Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Jul 21, 2017 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 16, 2023 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at