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

Total submissions: 17

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