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

gnomAD frequency: 0.00001  dbSNP: rs80358967

Total submissions: 13

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