ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9302T>G (p.Leu3101Arg) (rs28897758)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045787 SCV000073800 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 3101 of the BRCA2 protein (p.Leu3101Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast or ovarian cancer, and has been shown to segregate with breast cancer in several families (Invitae, external communications). This variant also occurs in trans with a pathogenic variant (p.Ala938Profs*21) in BRCA2 in an individual with clinical features of Fanconi anemia (external communication). ClinVar contains an entry for this variant (Variation ID: 38230). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162632 SCV000213068 pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 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). <span style="background-color:initial">This amino acid position is well conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). <span style="background-color:initial">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 RCV000657062 SCV000567965 likely pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9302T>G at the cDNA level, p.Leu3101Arg (L3101R) at the protein level, and results in the change of a Leucine to a Glycine (CTG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 9530T>G. This variant was observed with a BRCA2 pathogenic variant in a patient with Fanconi anemia and in trans with a BRCA2 pathogenic variant in a fetus with symptoms consistent with Fanconi anemia (Dueber 2013, ClinVar VCV000038230.2). BRCA2 Leu3101Arg was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider BRCA2 Leu3101Arg to be a likely pathogenic variant.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045787 SCV000800821 pathogenic Hereditary breast and 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 Health, Inc RCV000162632 SCV000903964 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045787 SCV001362773 pathogenic Hereditary breast and 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 RCV001287357 SCV001474032 likely pathogenic none 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
Sharing Clinical Reports Project (SCRP) RCV000031813 SCV000054421 uncertain significance Breast-ovarian cancer, familial 2 2012-05-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031813 SCV000147606 uncertain significance Breast-ovarian cancer, familial 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.

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