Submissions for variant NM_000059.4(BRCA2):c.241T>A (p.Phe81Ile)

dbSNP: rs80358507

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000043988	SCV000072001	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000586268	SCV000210434	uncertain significance	not provided	2022-11-17	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, prostate cancer, or melanoma (Kote-Jarai et al., 2011; Johansson et al., 2019; Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 469T>A; This variant is associated with the following publications: (PMID: 31464824, 33471991, 21952622, 25348012, 32641407)
Ambry Genetics	RCV000217504	SCV000272958	likely benign	Hereditary cancer-predisposing syndrome	2019-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000217504	SCV000683483	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 81 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). In a functional study, this variant showed 72% homology-directed repair capacity of wild-type BRCA2 (PMID: 35979650). This variant has been detected in a breast cancer case-control meta-analysis in 6/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001289) and also in an individual affected with prostate cancer (PMID: 21952622). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database and in 6/251364 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	RCV002295275	SCV000694607	uncertain significance	not specified	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.241T>A (p.Phe81Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.241T>A has been reported in the literature in individuals affected with various cancers, including prostate cancer (Kote-Jarai_2011, Johansson_2019), breast cancer (Dorling_2021) and cutaneous melanoma (Johansson_2019). The variant was also found at a carrier frequency of 0.0001365 in European American women over the age of 70 without history of cancer (FLOSSIES database). These reports 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, and a minigene splicing assay demonstrated that the variant had no impact splicing (Tubeuf_2020). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000031366	SCV000784869	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000043988	SCV000838725	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217504	SCV002535500	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
Human Genetics Bochum, Ruhr University Bochum	RCV000031366	SCV002758576	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-01	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PM2, BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586268	SCV004219539	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 21952622 (2011)) and melanoma (PMID: 31464824 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000053 (6/113686 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000031366	SCV004846751	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 81 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). In a functional study, this variant showed 72% homology-directed repair capacity of wild-type BRCA2 (PMID: 35979650). This variant has been detected in a breast cancer case-control meta-analysis in 6/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001289) and also in an individual affected with prostate cancer (PMID: 21952622). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database and in 6/251364 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)	RCV000031366	SCV000053971	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-06-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031366	SCV000146428	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586268	SCV002037289	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586268	SCV002038317	likely benign	not provided		no assertion criteria provided	clinical testing