Submissions for variant NM_000059.4(BRCA2):c.2944A>C (p.Ile982Leu)

gnomAD frequency: 0.00002  dbSNP: rs28897717

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167800	SCV000072103	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131312	SCV000186285	benign	Hereditary cancer-predisposing syndrome	2014-05-27	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	RCV000044090	SCV000210296	likely benign	not specified	2018-02-15	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000587861	SCV000225161	uncertain significance	not provided	2015-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587861	SCV000600535	likely benign	not provided	2022-10-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131312	SCV000683513	likely benign	Hereditary cancer-predisposing syndrome	2018-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587861	SCV000694651	likely benign	not provided	2017-08-24	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2944A>C (p.Ile982Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 5/120330 control chromosomes at a frequency of 0.0000416, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature in an affected individual, without strong evidence for causality. Three clinical diagnostic laboratories classified this variant as uncertain significance, and one other lab classified it as benign, all without evidence for independent evaluaiton. UMD and BIC databases cite this variant in three individuals as co-occurring with pathogenic variants BRCA1 c.4327C>T (p.Arg1443X), BRCA1 c.4964_4982del (p.Ser956=fs), and BRCA2 c.7638-7647del (p.Lys257X), respectively, supporting the non-pathogenic role of this variant. Taken together, this variant is classified as likely benign.
GeneKor MSA	RCV000131312	SCV000821931	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131312	SCV002533746	likely benign	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131312	SCV003850259	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000044090	SCV004027412	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113118	SCV000146144	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353864	SCV000591837	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	BRCA2, EXON11, c.2944A>C, p.Ile982Leu, Heterozygous, Likely Benign The BRCA2 p.Ile982Leu variant was identified in 1 of 512 proband chromosomes (frequency: 0.002) from French Canadian individuals or families with hereditary breast and/or ovarian cancer (Simard 2007). The variant was also identified in dbSNP (ID: rs28897717) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, Quest Diagnostics, Invitae, BIC and our laboratory; and as benign by Ambry Genetics), LOVD 3.0 (3 entries, effect unknown or not classified), UMD-LSDB (9 entries for this variant including one patient with a co-occurring, pathogenic BRCA2 mutation (c.7638_7647del, p.Lys254X) and another with a co-occurring, pathogenic BRCA1 mutation (c.4327C>T, p.Arg1443X), and the BIC Database (11 entries, classification pending). The variant was also identified by our laboratory in 2 individuals with breast cancer, however this variant does not appear to segregate with disease as the affected mother of one of these patients is negative for this variant, decreasing the likelihood that this variant may have clinical significance. The variant was identified in control databases in 8 of 244434 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5442 chromosomes (freq: 0.0002), European Non-Finnish in 7 of 110922 chromosomes (freq: 0.00006), but not in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ile982Leu 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 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. 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	RCV000587861	SCV000778657	benign	not provided	2024-05-01	no assertion criteria provided	clinical testing	BS1_sup, BS4, BP1_strong, BP5_mod
True Health Diagnostics	RCV000131312	SCV000787925	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113118	SCV004228392	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)