Submissions for variant NM_000059.4(BRCA2):c.8668C>A (p.Leu2890Ile)

gnomAD frequency: 0.00001  dbSNP: rs80359127

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082637	SCV000073610	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131717	SCV000186756	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	The p.L2890I variant (also known as c.8668C>A), located in coding exon 20 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8668. The leucine at codon 2890 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in 1/257 Brazilian patients with suspected hereditary breast/ovarian cancer syndrome (HBOC) (Matta BP et al. Sci Rep, 2022 Nov;12:18629). This alteration was also detected in a prostate cancer patient who was either diagnosed <65y or diagnosed >65y with a family history of prostate cancer (Kote-Jarai Z et al. Br J Cancer. 2011 Oct 11;105:1230-4). This alteration is predicted to be neutral or stabilizing by other models and in silico tools (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Doss CG et al. Cell Biochem. Biophys. 2014 Nov;70:939-56). 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.
Eurofins Ntd Llc (ga)	RCV000587037	SCV000227749	uncertain significance	not provided	2014-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000587037	SCV000278882	uncertain significance	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8896C>A; This variant is associated with the following publications: (PMID: 19043619, 24817641, 31911673, 29884841, 28591715, 12228710, 36329109, 32377563, 21952622, 31853058, 28726806)
Counsyl	RCV000077447	SCV000489154	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175344	SCV000695171	likely benign	not specified	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8668C>A (p.Leu2890Ile) 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. The variant allele was found at a frequency of 1.6e-05 in 251326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8668C>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Karchin_2008) and other cancer phenotypes (example, Kote-Jarai_2011, Deihimi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRCA1 c.3340G>T, p.Glu1114*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (Likely benign, n=2; VUS, n=9). Some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077447	SCV000744545	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131717	SCV000911249	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 2890 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 36329109), an individual affected with colorectal cancer (PMID: 28591715), and an individual affected with prostate cancer (PMID: 21952622). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 3/60466 cases and 2/53461 controls (OR=1.326, 95%CI 0.222 to 7.938; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000363). This variant has also been identified in 5/282728 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587037	SCV001133942	uncertain significance	not provided	2019-12-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000077447	SCV001139224	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001082637	SCV001737426	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-04-29	criteria provided, single submitter	clinical testing	The BRCA2 c.8668C>A (p.Leu2890Ile) missense change has a maximum frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32950842-C-A?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, and to our knowledge functional assays have not been performed. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). This variant was reported in an individual with prostate cancer who was either diagnosed <65 years of age or diagnosed >65 years of age with a family history of prostate cancer (PMID: 21952622). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no applicable criteria.
Genetics Program, Instituto Nacional de Cancer	RCV001082637	SCV002515156	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
MGZ Medical Genetics Center	RCV003607220	SCV002580133	uncertain significance	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP4
All of Us Research Program, National Institutes of Health	RCV000077447	SCV004846053	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 2890 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast or ovarian cancer (PMID: 36329109), an individual affected with colorectal cancer (PMID: 28591715), and an individual affected with prostate cancer (PMID: 21952622). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 3/60466 cases and 2/53461 controls (OR=1.326, 95%CI 0.222 to 7.938; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000363). This variant has also been identified in 5/282728 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)	RCV000077447	SCV000109245	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077447	SCV000147435	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587037	SCV001906452	likely benign	not provided		no assertion criteria provided	clinical testing