Submissions for variant NM_000059.4(BRCA2):c.8009C>T (p.Ser2670Leu)

gnomAD frequency: 0.00001  dbSNP: rs80359035

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045385	SCV000073398	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2670 of the BRCA2 protein (p.Ser2670Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer or Fanconi anemia (PMID: 15131399, 22895246, 23096355, 24249303, 24735155, 26187060, 26250392, 28176296, 31409081, 31742824, 31843900, 34717758). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 8237C>T. ClinVar contains an entry for this variant (Variation ID: 52471). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 29394989, 32444794). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000131082	SCV000186012	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.S2670L pathogenic mutation (also known as c.8009C>T), located in coding exon 17 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8009. The serine at codon 2670 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with clinical histories suggestive of HBOC (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Jimenez AM et al. Clin. Adv. Hematol. Oncol. 2012 Jun;10:402-4; Lara K et al. Biol. Res. 2012;45(2):117-30; Lynce F et al. Breast Cancer Res. Treat. 2015 Aug;153:201-9; Pal T et al. Cancer. 2015 Dec;121:4173-80). This alteration has been identified with multiple pathogenic BRCA2 alterations in multiple families with Fanconi Anemia (Rosenthal ET et al. Clin. Genet. 2015 Dec;88(6):533-41; Trejo Bittar HE et al. Pediatr. Dev. Pathol. 2014 Apr;17:297-301). This variant was found to be functionally defective in a homology-directed repair assay (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80). This alteration was shown to result in a minor amount of exon 17 skipping (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691). Of note, this alteration is also designated as 8237C>T in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx	RCV000212267	SCV000210458	likely pathogenic	not provided	2024-11-06	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 16489001, 23096355, 22895247, 22895246, 26250392, 26287763, 26187060, 28294317, 28176296, 28724667, 30254663, 32856869, 32438681, 31742824, 35155181, 35641994, 35864222, 36881271); Observed in trans with a pathogenic BRCA2 variant in individuals with Fanconi anemia, but also in the unaffected sibling of one of these individuals (PMID: 24735155, 25639900); Published functional studies demonstrate a damaging effect: impaired homology directed repair activity and sensitivity to PARP inhibitors (PMID: 29394989, 29884841, 32444794); Multifactorial likelihood analysis suggests this variant is likely pathogenic (PMID: 31131967, 34597585); In silico analysis indicates that this missense variant does not alter protein structure/function; Variant demonstrated aberrant splicing, resulting in a minor amount of partial skipping of exon 18 (PMID: 28339459); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8237C>T; This variant is associated with the following publications: (PMID: 15131399, 26187060, 26250392, 26681312, 24249303, 28591715, 24735155, 34717758, 21702907, 22895246, 16489001, 23096355, 25639900, 26287763, 19043619, 23303603, 22895247, 28476184, 28281021, 28724667, 29394989, 16489007, 18951461, 29395620, 28176296, 28294317, 30254663, 29884841, 30702160, 32444794, 32318955, 32438681, 32772458, 31742824, 28692638, 33293522, 32856869, 31825140, 32467295, 30787465, 34597585, 35665744, 35861108, 31131967, 35864222, 35155181, 36881271, 37789896, 35641994, 32073954, 28339459, 34235180, 37937776, 36721989, 33471991, 34413315, 33461583, 36367610, 38671360, 38948361, 33850850, 12228710)
UOSD Diagnostica Molecolare E Genomica, Irccs Policlinico Agostino Gemelli	RCV000409052	SCV000484655	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-12-14	criteria provided, single submitter	clinical testing	Personal and familial history of breast and ovarian cancers
Color Diagnostics, LLC DBA Color Health	RCV000131082	SCV000683935	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2670 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies reported this variant results in the production of BRCA2 protein that is severely impaired in homology-directed repair assays (PMID: 19043619, 29394989). An RNA study found the variant resulted in splicing defects predicted to cause an absent or non-functional protein product (PMID: 31843900). This variant has been observed in multiple individuals affected with breast cancer (PMID: 22895246, 25639900, 26681312, 31843900), pancreatic cancer (PMID: 29395620) and ovarian cancer (PMID: 33850850). This variant also has been observed in multiple families affected with breast and/or ovarian cancer (PMID: 15131399, 24249303, 30254663) and it is reported to co-segregate with disease in two families with likelihood ratio of 17.8658 (PMID: 31131967). This variant is also seen in an individual with a pathogenic BRCA2 covariant affected with Fanconi anemia and has a family history of breast and other solid-tumor cancers (PMID: 24735155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000077423	SCV000786255	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212267	SCV000889147	likely pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000013 (2/151936 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMID: 33471991 (2021), 34413315 (2021), 31742824 (2020), 31843900 (2019), 30254663 (2018), 28724667 (2017), 28476184 (2017), 26681312 (2015), 26287763 (2015), 26250392 (2015)). In addition, it has been reported in trans with two different suspect BRCA2 variants in individuals with features of Fanconi Anemia (PMID: 25639900 (2015), 24735155 (2014)). Experimental studies indicate that this variant has a damaging effect on the expression and function of the BRCA2 protein in vitro (PMID: 31843900 (2019), 29394989 (2018), 28339459 (2017), 19043619 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045385	SCV001426773	pathogenic	Hereditary breast ovarian cancer syndrome	2020-07-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8009C>T (p.Ser2670Leu) results in a non-conservative amino acid change located in the DSS1 interaction domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251148 control chromosomes. c.8009C>T has been reported in the literature in multiple individuals affected with Hereditary/Familial Breast And Ovarian Cancer and at-least two individuals with Fanconi Anemia in whom a co-occurring BRCA2 variant in trans was identified (example, Lubinski_2004, Lara_2012, Chenevix-Trench_2006, Hondow_2011, Nakamura_2015, Jimnez_2012, Lynce_2015, Machakova_2019, Rosenthal_2015, Shao_2020, Susswein_2016, Zuntini_2018, Trejo Bittar_2014). These data indicate that the variant allele was transmitted much more often than the reference allele to affected individuals within families and is therefore likely to be associated with disease. The cases with other co-occurring pathogenic variants include, BRCA2 c.9699_9702delTATG, p.Cys3233_Met3234?fs (p.Cys3233fs) and BRCA2 c.767insA (variant not reported in other databases) respectively in two patients with Fanconi Anemia (Rosenthal_2015 and Trejo Bittar_2014); and BRCA1 c.212+3A>G (UMD database). At least three independent publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed DNA repair (HDR) capability (Hart_2019, Guidugli_2018, Karchin_2008). Loss of heterozygosity (LOH) of the variant allele was observed in at-least one of two tumors examined, while no LOH was observed in the second tumor (Chenevix-Trench_2006). To our knowledge, this finding has not been independently reproduced and the authors speculated that the loss of the wild-type allele is less common for some pathogenic missense variants that act as dominant-negative mutations. Therefore, this evidence is not weighted in favor of a neutral impact of this variant in-vivo. Two recent publications, one reporting the fifth Critical Assessment of Genome Interpretation (CAGI) and another reporting a multifactorial analysis based classification, both support a "likely pathogenic" outcome for this variant (Padilla_2019, Parsons_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045385	SCV001478293	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-10	criteria provided, single submitter	curation	Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (28.4) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.99 and an overall classification of pathogenic. (PS3_strong). This variant has been classified on ClinVar as likely pathogenic by multiple accredited USA diagnostic laboratories (PP5_sup). Data not used in classification: There are additional reports of this variant in UMD (6), BIC (9), and BRCA2 LOVD (2).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212267	SCV002010319	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Mendelics	RCV001762153	SCV002518606	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504936	SCV002810379	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001762153	SCV003834800	likely pathogenic	Familial cancer of breast	2024-02-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212267	SCV005090056	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077423	SCV000109221	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077423	SCV000147248	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496611	SCV000587931	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001270290	SCV000592170	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2670Leu variant has been reported in individuals affected with breast cancer (PMID: 23096355, 26250392) and inflammatory breast cancer (PMID: 22895246), as well as in individuals with a personal and/or family history of breast/ovarian cancer (PMID: 15131399, 24249303, 26187060). This variant was also observed to co-occur with a pathogenic BRCA2 variant (c.538_539dupAT) in an individual with Fanconi anemia, however the phase of the variants was not confirmed (PMID: 24735155). The variant was identified in ClinVar (Conflicting interpretations of pathogenicity. Likely pathogenic: Ambry in 2017, GeneDx in 2017, Counsyl in 2017, Invitae in 2018, Color in 2018, Quest Diagnostics in 2019, Sharing Clinical Reports Project in 2010. VUS by Research Molecular Genetics Laboratory at Women's College Hospital in 2014. Pathogenic by Clinical molecular and personalized diagnostics in 2016. GeneInsight-COGR (Sinai Health System and COGR consensus) classify as VUS, 2013), LOVD 3.0 (17 entries, VUS 10x, likely pathogenic 3x, pathogenic 1x) and __ARUP Laboratories (3-Uncertain) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). A truncating variant at the same location, c.8009C>A (p.Ser2670*), is classified in ClinVar as Pathogenic (3 stars, reviewed by expert panel). The variant is located in the BRCA2 DNA binding domain (Yang 2002, Guidugli 2017), increasing the likelihood that it may have clinical significance. Through a homology-directed DNA repair assay, the p.Ser2670Leu variant was found to substantially decrease HDR compared to wild-type BRCA2 and known neutral variants, and was predicted to be deleterious (Guidugli_2017_PMID:29394989). However, Karchin (2008) and Chenevix-Trench (2006) described this variant on an allele that was lost by LOH in breast tissue, a result that has been associated with increased probability of neutrality. Furthermore, Myriad genetics has also reported this variant to co-occur with a second pathogenic variant (Chenevix-Trench 2006) increasing the likelihood this variant may be benign. The p.Ser2670 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 pathogenic role for this variant. This variant is classified as likely pathogenic.
King Laboratory, University of Washington	RCV001171451	SCV001251362	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732625	SCV005346982	likely pathogenic	BRCA2-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The BRCA2 c.8009C>T variant is predicted to result in the amino acid substitution p.Ser2670Leu. This variant has been reported in multiple individuals with hereditary breast and ovarian cancer (see for example, Jimenez et al. 2012. PubMed ID: 22895246; Lynce et al. 2015. PubMed ID: 26250392; Sun et al. 2017. PubMed ID: 28724667) and has been reported in the compound heterozygous state in at least two patients with clinical features of Fanconi Anemia (Trejo Bittar et al. 2014. PubMed ID: 24735155; Rosenthal et al. 2015. PubMed ID: 25639900). Additionally, studies using a homology directed DNA repair activity assay showed this variant is functionally defective (Hart et al. 2018. PubMed ID: 29884841; Guidugli et al. 2012. PubMed ID: 23108138). This variant has not been reported in a large population database such as gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52471/?new_evidence=true). This variant is interpreted as likely pathogenic.