Submissions for variant NM_000059.4(BRCA2):c.4061C>T (p.Thr1354Met)

gnomAD frequency: 0.00014  dbSNP: rs80358656

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077319	SCV000244445	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000803
Invitae	RCV001085458	SCV000072352	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000077319	SCV000154102	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-12	criteria provided, single submitter	literature only
CSER _CC_NCGL, University of Washington	RCV000148432	SCV000190131	likely benign	Breast neoplasm	2014-06-01	criteria provided, single submitter	research
GeneDx	RCV001353774	SCV000210601	likely benign	not provided	2021-03-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 12845657, 21520273, 21156238, 21990134, 24055113, 25637381, 24323938, 24728327, 26306726, 11336395, 20104584, 16847550, 20960228, 26689913, 24504028, 27153395, 28202063)
Ambry Genetics	RCV000163005	SCV000213493	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000120326	SCV000334467	likely benign	not specified	2015-09-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120326	SCV000593744	likely benign	not specified	2016-04-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163005	SCV000679715	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163005	SCV000683597	likely benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120326	SCV000694739	benign	not specified	2019-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4061C>T (p.Thr1354Met) 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 0.00014 in 243646 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00014 vs 0.00075), allowing no conclusion about variant significance. The variant, c.4061C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Arver_2001 , Capalbo_2006 , deSanjose_2003 , Laitman_2011) without strong evidence for causality. Cosegregation studies in a family with a history of breast cancer found that this variant did not segregate with disease (Jalkh_2017). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.2071_2071delA, p.Arg691Aspfs (BIC database), CDH1 c.3G>A, p.Met1Ile (Jalkh_2017)], providing supporting evidence for a benign role. Ten other submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as benign (n=3) or likely benign (n=7). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077319	SCV000743293	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077319	SCV000744449	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000120326	SCV000864300	likely benign	not specified	2017-12-29	criteria provided, single submitter	clinical testing	BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Mendelics	RCV000077319	SCV001139080	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001353774	SCV001472635	likely benign	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163005	SCV002533841	likely benign	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120326	SCV002550330	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001353774	SCV002822066	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149678	SCV003838823	likely benign	Breast and/or ovarian cancer	2021-06-08	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077319	SCV004016875	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001085458	SCV004228070	likely benign	Hereditary breast ovarian cancer syndrome	2023-08-04	criteria provided, single submitter	clinical testing
ITMI	RCV000120326	SCV000084478	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077319	SCV000109116	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077319	SCV000146367	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	RCV001353774	SCV000591886	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Thr1354Met variant was identified in 6 of 5256 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast or ovarian cancer (Giannini 2006, Borg 2010, de Sanjosé 2003, Yang 2011). The variant was also identified in the following databases: dbSNP (ID: rs80358656) as ” With other allele”, ClinVar (17 x as benign by ENIGMA, VKGL data share, Invitae, Ambry Genetics, SCRP, as likely benign by EGL Genetics, COGR, Color Genomics, Integrated Genetics, Counsyl, GeneDx and as uncertain significance by BIC), COGR (as likely benign/benign), Cosmic (1x confirmed somatic ovarian carcinoma), LOVD 3.0 (7x as benign or predicted neutral), UMD-LSDB (17 x as likely neutral), BIC Database (12 x as uncertain significance), ARUP Laboratories (as “class 1,not pathogenic or of no clinical significance”). The variant was not identified in MutDB or Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 3 individuals with hereditary breast or ovarian cancer and 3 different co-occurring pathogenic variants were identified in each of these individuals (BRCA2, c.7007G>C, p.Arg2336Pro), (BRCA1, c.4096+1G>A, r.spl?) and (BRCA2, c.1103C>A, p.Ser368*), increasing the likelihood that the p.Thr1354Met variant does not have clinical significance. The variant was identified in control databases in 34 of 269620 chromosomes at a frequency of 0.00013 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23878 chromosomes (freq: 0.00004), Other in 2 of 6330 chromosomes (freq: 0.0003), Latino in 4 of 32684 chromosomes (freq: 0.0001), European Non-Finnish in 22 of 124492 chromosomes (freq: 0.00018), Ashkenazi Jewish in 4 of 9770 chromosomes (freq: 0.0004), and South Asian in 1 of 28178 chromosomes (freq: 0.000035); the variant was not observed in the East Asian or European Finnish populations. The p.Thr1354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein (Capanu 2011, Easton 2007, Lindor 2012); this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120326	SCV001952259	benign	not specified		no assertion criteria provided	clinical testing