Submissions for variant NM_000059.4(BRCA2):c.7010C>T (p.Thr2337Ile)

gnomAD frequency: 0.00004  dbSNP: rs80358927

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203621	SCV000073133	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2337 of the BRCA2 protein (p.Thr2337Ile). This variant is present in population databases (rs80358927, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer and in individuals in the Breast Cancer Information Core database. However, in one of these individuals a pathogenic variant was also identified in BRCA1, which suggests that this c.7010C>T BRCA2 variant was not the primary cause of disease (PMID: 10923033, 15800311, 16683254, 27376475). ClinVar contains an entry for this variant (Variation ID: 52248). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 35762214). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000130807	SCV000185703	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The p.T2337I variant (also known as c.7010C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7010. The threonine at codon 2337 is replaced by isoleucine, an amino acid with similar properties. This variant has been reported in multiple individuals and/or families who met eligibility criteria for hereditary breast and/or ovarian cancer syndrome (Gómez-García EB et al. J Clin Oncol, 2005 Apr;23:2185-90; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Schenkel LC et al. J Mol Diagn, 2016 09;18:657-667; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000656800	SCV000210412	uncertain significance	not provided	2022-01-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7238C>T; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Gomez-Garcia 2005, van der Hout 2006); This variant is associated with the following publications: (PMID: 31131967, 16683254, 15800311, 27376475)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656800	SCV000600730	uncertain significance	not provided	2021-02-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130807	SCV000911244	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 2337 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not impact cell viability or drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). This variant has been detected in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 15800311, 16683254, 27376475, 32885271) and in a breast cancer case-control meta-analysis in 5/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001509). This variant also has been detected in unaffected individuals (PMID: 24448499; FLOSSIES database). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.5103, respectively (PMID: 31131967). This variant has been identified in 7/281770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358764	SCV001554634	uncertain significance	not specified	2021-03-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7010C>T (p.Thr2337Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7010C>T has been reported in the literature in a family undergoing complete BRCA 1 and 2 mutational analyses, a patient with Ovarian Cancer and in a family of Breast and/or Ovarian cancer (GomezGarcia_2005, Kanchi_2014, vanderHout_2006). Co-occurrence with anther pathogenic variant has been reported (BRCA1 c.2331T>A, p.Tyr777Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetics and Molecular Pathology, SA Pathology	RCV000113691	SCV002761559	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113691	SCV004844347	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 2337 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 15800311, 16683254, 27376475) and in a breast cancer case-control meta-analysis in 5/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001509). This variant also has been detected in unaffected individuals (PMID: 24448499; FLOSSIES database). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.5103, respectively (PMID: 31131967). This variant has been identified in 7/281770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004566832	SCV005059026	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113691	SCV000147000	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113691	SCV000733291	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358531	SCV001554292	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Thr2337Ile variant was identified in 2 of 1666 proband chromosomes (frequency: 0.001) from Dutch and Canadian individuals or families with breast or ovarian cancer (van der Hout 2006, Schenkel 2016). The variant was identified in dbSNP (ID: rs80358927) as “With other allele”, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and 3 other submitters; and as likely benign by Diagnostic Laboratory University Medical Center Groningen), and LOVD 3.0. The variant was not identified in UMD-LSDB. The variant was identified in control databases in 6 of 277036 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), and was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002) and European Non-Finnish in 5 of 126590 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Thr2337 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Thr2337Ile variant occurs in third base of the exon, outside of the splicing consensus sequence, and computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a significant difference in splicing. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000656800	SCV001906284	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656800	SCV001959898	likely benign	not provided		no assertion criteria provided	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266918	SCV002549696	uncertain significance	Chordoma	2021-03-22	no assertion criteria provided	research	No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function)