Submissions for variant NM_000059.4(BRCA2):c.1096T>G (p.Leu366Val)

gnomAD frequency: 0.00006  dbSNP: rs587779357

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586794	SCV000108595	likely benign	not provided	2019-08-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21769658, 21120943, 24884479, 23315985, 15937982)
Ambry Genetics	RCV000166352	SCV000217140	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.L366V variant (also known as c.1096T>G), located in coding exon 9 of the BRCA2 gene, results from a T to G substitution at nucleotide position 1096. The leucine at codon 366 is replaced by valine, an amino acid with highly similar properties. This alteration was previously reported in a woman diagnosed with ovarian cancer at age 47 and was not associated with aberration in splicing based on RT-PCR (Thomassen M et al. Breast Cancer Res Treat. 2012 Apr;132:1009-23). This variant was also reported in 1/120 Brazilian breast cancer patients from HBOC families and was considered a variant of uncertain significance (Silva FC et al. BMC Med. Genet. 2014 May;15:55). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087766	SCV000254167	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586794	SCV000600462	uncertain significance	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 15937982 (2005), 24884479 (2014), 35980532 (2022)), ovarian cancer (PMID: 21769658 (2012)), and hepatoblastoma (PMID: 35495172 (2022)). This variant is also reported in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00015 (5/34252 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000166352	SCV000683401	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 366 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 15937982, 21120943, 21769658, 24884479) and in unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002071). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, and co-occurrence likelihood ratios for pathogenicity of 0.9391, 1.07, and 1.025, respectively (PMID: 31131967). This variant has been identified in 7/249022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074510	SCV000694507	uncertain significance	not specified	2021-06-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1096T>G (p.Leu366Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 2/5 splice prediction tools predict that this variant may create a novel 3' splicing acceptor site. However, one study showed that aberrant splicing was not found in a patient who carries this variant (Thomassen_2011). The variant allele was found at a frequency of 2.8e-05 in 249022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096T>G has been reported in the literature in individuals affected with breast and ovarian cancer (example, Velasco_2005, Thomassen_2011, Silva_2014, Caux-Montcoutier_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3 and VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000077249	SCV001138987	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166352	SCV002533207	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166352	SCV003849833	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Myriad Genetics, Inc.	RCV000077249	SCV004018647	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-02	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
All of Us Research Program, National Institutes of Health	RCV000077249	SCV004846862	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 366 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 15937982, 21120943, 21769658, 24884479) and in unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002071). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, and co-occurrence likelihood ratios for pathogenicity of 0.9391, 1.07, and 1.025, respectively (PMID: 31131967). This variant has been identified in 7/249022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077249	SCV000109046	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843473	SCV002103120	likely pathogenic	Hepatoblastoma		no assertion criteria provided	research