ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6317T>C (p.Leu2106Pro) (rs56172926)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085349 SCV000072914 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131282 SCV000186251 likely benign Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000044901 SCV000210626 likely benign not specified 2017-12-19 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.
Color Health, Inc RCV000131282 SCV000683771 likely benign Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044901 SCV000694961 likely benign not specified 2021-05-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6317T>C (p.Leu2106Pro) 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. The variant allele was found at a frequency of 9e-05 in 244764 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (9e-05 vs 0.00075), allowing no conclusion about variant significance. c.6317T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Lee_2008, Borg_2010, Nguyen-Dumont_2020, Bishop_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One co-occurrence with another pathogenic variant has been reported (BRCA2 c.6209_6212delAAAG, p.Glu2070ValfsX10, UMD database), providing supporting evidence for a benign role. In addition, this variant has been reported in 3/9884 women (FLOSSIES database) who are cancer free and older than age 70, which further supports this variant is benign. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Biswas_2020). Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=5) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000077370 SCV000743317 likely benign Breast-ovarian cancer, familial 2 2015-01-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000077370 SCV000744485 likely benign Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Counsyl RCV000077370 SCV000786130 uncertain significance Breast-ovarian cancer, familial 2 2018-03-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112565 SCV001270230 uncertain significance Fanconi anemia, complementation group D1 2019-07-24 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000077370 SCV001270231 uncertain significance Breast-ovarian cancer, familial 2 2019-07-24 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Research and Development, ARUP Laboratories RCV001646505 SCV001854877 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077370 SCV000109167 benign Breast-ovarian cancer, familial 2 2011-03-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077370 SCV000146823 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044901 SCV000587834 benign not specified 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077370 SCV000592041 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Leu2106Pro variant was identified in 2 of 4434 proband chromosomes (frequency 0.0005) from individuals with breast or ovarian cancer (Borg 2010, Spearman 2008). The variant was also listed in the NHLBI Exome Sequencing Project with a frequency of 0.0002 in European American alleles, and was also identified in dbSNP, LOVD, the BIC database (13X as a variant with unknown clinical importance), and in UMD (4X as an unclassified variant). In UMD, the variant was listed to co-occur once with a pathogenic mutation in BRCA2 (c.6209_6212delAAAG (p.Glu2070ValfsX10)), increasing the likelihood that this variant does not have clinical importance. The p.Leu2106 residue is not conserved in mammals and the variant amino acid proline (Pro) is present in rat, cat and dog, also increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV001705700 SCV001906329 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001705700 SCV001953425 likely benign not provided no assertion criteria provided clinical testing

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