ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7448G>A (p.Ser2483Asn)

gnomAD frequency: 0.00001  dbSNP: rs80358967
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001082083 SCV000073233 likely benign Hereditary breast ovarian cancer syndrome 2024-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129898 SCV000184716 benign Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing 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.
GeneDx RCV000586632 SCV000210649 likely benign not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19043619, 18824701, 22476429, 27741520, 29884841)
Counsyl RCV000083134 SCV000487957 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2015-12-10 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine, Queen's University RCV000045220 SCV000588113 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129898 SCV000683873 likely benign Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045220 SCV000695068 benign not specified 2021-10-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7448G>A (p.Ser2483Asn) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) 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 1.6e-05 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7448G>A has been reported in the literature in individuals affected with breast cancer and also in individuals at risk of hereditary breast cancer (example, Spearman_2008, Carr_2011, Lu_2012, Fernandes_2016, Vendrell_2018) without strong evidence of causality. These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant(s) has been reported in the UMD database (BRCA2 c.7115C>G, p.Ser2372X), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (HDR) assays (example, Hart_2019, Richardson_2021) and in mouse embryonic stem cell-based functional assays that examined the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor (example, Biswas_2020). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). These findings are supported by a multifactorial probability model that reports a likely benign outcome (example, Parsons_2019). Ten 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 but with a predominant consensus as benign/likely benign (n=7) versus VUS (n=3). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586632 SCV001133897 likely benign not provided 2019-03-11 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586632 SCV001148990 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083134 SCV000115208 benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083134 SCV000147091 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000083134 SCV000592111 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing The BRCA2 p.Ser2483Asn variant was identified in 1 of 698 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and identified in 4 family members (Fernandes 2016). The variant was also identified in dbSNP (ID: rs80358967) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx and three other submitters; as uncertain significance by four submitters), COGR, MutDB, LOVD 3.0 (6x), UMD-LSDB (4x as unclassified variant), and in BIC Database (4x with unknown significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.7115C>G, p.Ser2372X), increasing the likelihood that the p.Ser2483Asn variant does not have clinical significance. The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 5 of 246090 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111588 chromosomes (freq: 0.000045), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser2483 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the p.Ser2483Asn variant was identified in the literature in two reports that use various prediction models to try to determine the clinical significance of this variant. Both reports imply that the variant is predicted neutral (Karchin 2008, Spearman 2008). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000586632 SCV000778709 likely benign not provided 2018-02-09 no assertion criteria provided clinical testing

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