rs138489917
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_000059.4(BRCA2):c.5495C>A(p.Ser1832Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. 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. S1832C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5495C>A | p.Ser1832Tyr | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5495C>A | p.Ser1832Tyr | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250668Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135568
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1461140Hom.: 0 Cov.: 44 AF XY: 0.00000688 AC XY: 5AN XY: 726766
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Borg et al., 2010; Momozawa et al., 2018; Dorling et al., 2021); Also known as 5723C>A; This variant is associated with the following publications: (PMID: 20104584, 28222693, 30311378, 30212499, 30287823, 31131967, 21520273, 32377563, 29884841, 33471991) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 31, 2023 | In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 33471991 (2021), 30287823 (2018), 21520273 (2011), 20104584 (2010)), as well as in unaffected individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In addition, this variant is reported to be located in a region of the BRCA2 gene that is tolerant to missense changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0002 (4/19950 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2021 | The BRCA2 c.5495C>A; p.Ser1832Tyr variant (rs138489917) has been reported in the literature in multiple individuals with breast cancer, but without evidence of pathogenicity (Borg 2010, Momozawa 2018). This variant is reported in ClinVar (Variation ID: 91415), and observed in the East Asian population at an overall frequency of 0.021% (4/18860 alleles) in the Genome Aggregation Database. The serine at codon 1832 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.409). This variant has been detected in an individual who also harbored a pathogenic BRCA1 variant, suggesting that BRCA2 p.Ser1832Tyr does not contribute to hereditary breast and ovarian cancer risk. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. PMID: 20104584. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8. PMID: 30287823. - |
Hereditary cancer-predisposing syndrome Benign:3
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 | Jan 03, 2017 | 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 | Jun 21, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Sep 12, 2012 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | - - |
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.Ser1832Tyr variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Borg 2010). The variant was also identified in dbSNP (ID: rs138489917) as With Uncertain significance allele, ClinVar (classified as likely benign by Ambry Genetics, Invitae, SCRP; classified as uncertain significance by GeneDx), Genesight-COGR (classified as unknown significance), UMD-LSDB (2X uncertain significance), databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 5 of 276638 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ser1832 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the Breast cancer type 2 susceptibility protein functional domain increasing the likelihood that it may have clinical significance. In addition, in an in silico study of 2103 women with unilateral and contralateral breast cancer the variant was found in patient with unilateral breast cancer and determined unclassified (Borg 2010). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2024 | Variant summary: BRCA2 c.5495C>A (p.Ser1832Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250668 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5495C>A has been reported in the literature in individuals affected with breast cancer (e.g. Borg_2010, Momozawa_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. A study using multifactorial probability likelihood analysis reported this variant as strong in favour of a benign outcome (Parsons_2019). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.5096G>A, p.Arg1699Gln), 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: 20104584, 21520273, 30287823, 28222693, 31131967). ClinVar contains an entry for this variant (Variation ID: 91415). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely 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