Submissions for variant NM_000059.4(BRCA2):c.3088T>G (p.Phe1030Val)

gnomAD frequency: 0.00001  dbSNP: rs80358554

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044116	SCV000072129	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165765	SCV000216510	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-11	criteria provided, single submitter	clinical testing	The p.F1030V variant (also known as c.3088T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 3088. The phenylalanine at codon 1030 is replaced by valine, an amino acid with highly similar properties. This variant was reported to be absent from 60,466 breast cancer cases and present in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Another study reported the variant in an individual with hereditary breast and ovarian cancer (Caux-Moncoutier V et al. Eur J Hum Genet, 2009 Nov;17:1471-80). This alteration was classified as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is poorly 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.
GeneDx	RCV000214139	SCV000278844	uncertain significance	not provided	2017-08-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3088T>G at the cDNA level, p.Phe1030Val (F1030V) at the protein level, and results in the change of a Phenylalanine to a Valine (TTC>GTC). Using alternate nomenclature, this variant would be defined as BRCA2 3316T>G. A cDNA-based investigation, following identification of this variant in at least one individual with a history suggestive of hereditary breast and ovarian cancer, determined that this variant did not demonstrate allelic imbalance (Caux-Moncoutier 2009); however, follow-up confirmatory studies have not been published, to our knowledge. BRCA2 Phe1030Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Valine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Phe1030Val occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is located in the BRC1 domain and RAD51 binding domain (Cole 2011, Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Phe1030Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165765	SCV000688785	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 1030 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). A functional study in mouse embryonic stem cells showed that this variant does not impact cell viability or drug sensitivity (PMID: 37922907). This variant has been reported in an individual affected with breast or ovarian cancer and in two unaffected individuals (PMID: 19471317, 33471991; Leiden Open Variation Database DB-ID BRCA2_001408). This variant has been identified in 3/250076 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.
Mendelics	RCV000044116	SCV000838783	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214139	SCV000889016	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual with hereditary breast and/or ovarian cancer (PMID: 19471317 (2009)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). The frequency of this variant in the general population, 0.000012 (3/250076 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Results from a multifactorial likelihood analysis indicate this variant is neutral (PMID: 31131967 (2019)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000077291	SCV001139056	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165765	SCV002533762	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-12	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165765	SCV003851675	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).
Sharing Clinical Reports Project (SCRP)	RCV000077291	SCV000109088	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077291	SCV000146168	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-08-16	no assertion criteria provided	clinical testing