Submissions for variant NM_000059.4(BRCA2):c.9302T>G (p.Leu3101Arg)

dbSNP: rs28897758

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045787	SCV000073800	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3101 of the BRCA2 protein (p.Leu3101Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast or ovarian cancer (Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38230). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162632	SCV000213068	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-31	criteria provided, single submitter	clinical testing	The p.L3101R pathogenic mutation (also known as c.9302T>G), located in coding exon 24 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9302. The leucine at codon 3101 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in a fetus who is compound heterozygous for this alteration and a BRCA2 frameshift mutation whose clinical features are highly suggestive of Fanconi Anemia (personal communication). In addition, this alteration was defective in a homology-directed repair assay (Ambry internal data). This variant was observed to segregate with breast cancer in multiple families (Ambry internal data). Based on internal structural assessment this alteration is expected to result in significant destabilization of OBD3, in which other destabilizing pathogenic alterations are present (Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000657062	SCV000567965	likely pathogenic	not provided	2019-12-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19043619, 18724707, 25859162, 28726806, 32719484)
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045787	SCV000800821	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-13	criteria provided, single submitter	clinical testing	Data used in classification: The variant was observed in 10 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. The diagnosis of hereditary breast and/or ovarian cancer was confirmed in probands. The probands were confirmed as White British in all but two families (for which ethnicity not reported). Case control comparison against ethnically matched population data (10/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) passoc=6.53x10-10 pexact= 1.49x10-7 (PS4_very strong). An additional 5 families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA2 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). In addition on testing in the UK of a fetus with a clinical diagnosis of Fanconi Anaemia D1, this variant was found in trans with a pathogenic truncating variant in BRCA2 (parental genotypes confirmed) (PM3). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3).
Color Diagnostics, LLC DBA Color Health	RCV000162632	SCV000903964	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 3101 in the DNA binding/OB tower domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair assays (PMID: 32377563, 35736817). This variant has been detected in at least four individuals affected with breast cancer and in dozens of individuals who underwent cancer genetic testing (PMID: 32170000, 33471991; Leiden Open Variation Database DB-ID BRCA2_000444; Color internal data) and in an individual affected with sarcoma (PMID: 27498913). A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.1157, 3.623, 1.1293 and 0.191, respectively (PMID: 31131967). This variant also has been reported in a compound heterozygous carrier who has clinical phenotype consistent with Fanconi anemia (PMID: 33609447; ClinVar variation ID 38230). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045787	SCV001362773	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9302T>G (p.Leu3101Arg) results in a non-conservative amino acid change located in the BRCA2, OB3 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 250968 control chromosomes (gnomAD). c.9302T>G has been reported in the literature in individuals/families affected with Hereditary Breast and Ovarian Cancer (McRonald_2019, ClinVar SCV000800821.1), and also in individuals affected with Fanconi anemia who were reported with additional BRCA2 pathogenic variants presumed or confirmed to be in trans (Dueber_2013, ClinVar SCV000073800.8). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to be damaging (Hart_2019). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=3) and as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657062	SCV001474032	likely pathogenic	not provided	2020-03-06	criteria provided, single submitter	clinical testing	The BRCA2 c.9302T>G; p.Leu3101Arg variant (rs28897758) is reported in the literature in an infant with fanconi anemia who carried a BRCA2 pathogenic variant presumably on the opposite allele (Dueber 2013). This variant is also reported in the ClinVar database (Variation ID: 38230). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 3101 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Dueber J.C., Mosse C., Alford C.E. et al. Precursor T acute lymphoblastic leukemia from myelodysplastic syndrome in Fanconi anemia. J Hematopathol 6, 161–165 (2013). https://doi.org/10.1007/s12308-012-0168-2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798057	SCV002041912	likely pathogenic	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473230	SCV004212907	likely pathogenic	Familial cancer of breast	2021-09-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657062	SCV004220650	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with personal and family history of breast cancer, as well as in two fetuses (siblings) who were determined to carry an additional BRCA pathogenic variant in trans and diagnosed with Fanconi anemia (personal communication, see Kobelka, C et al., https://brca2021.ipostersessions.com/?s=B7-A7-93-51-9C-E3-B5-01-75-60-B7-01-E1-9F-65-91). In addition, an experimental study has shown this variant is damaging to BRCA2 HDR activity (PMID: 33609447 (2021)). 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 pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031813	SCV000054421	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031813	SCV000147606	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657062	SCV000592275	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Leu3101Arg variant was identified in dbSNP (ID: rs28897758) as “With uncertain significance allele”, Clinvitae database (classification uncertain significance), Fanconi Anemia Mutation Database (LOVD), the ClinVar database (classification uncertain significance by Invitae, Ambry Genetics, BIC and Sharing Clinical Reports Project derived from Myriad reports), GeneInsight COGR database (classification uncertain significance by 2 clinical laboratories), and the BIC database (2x with unknown clinical importance). The variant was not identified in the 1000 Genomes Project, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2016) database, COSMIC, and LOVD IARC. The p.Leu3101 residue is not conserved across mammals and other organisms, and 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, HumanSpliceFinder) do not predict a difference in splicing. One in silico study using a protein likelihood ratio, suggests that this variant is likely deleterious (Karchin 2008). However, this information is not predictive enough to assume pathogenicity, and segregation and/or additional functional studies are recommended to further elucidate the pathogenicity of this variant. 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.