Submissions for variant NM_000059.4(BRCA2):c.3987A>T (p.Arg1329Ser)

dbSNP: rs786203361

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166638	SCV000217442	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	The p.R1329S variant (also known as c.3987A>T and 4215A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 3987. The arginine at codon 1329 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not 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.
GeneDx	RCV000236432	SCV000292528	uncertain significance	not provided	2016-04-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3987A>T at the cDNA level, p.Arg1329Ser (R1329S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGT). This variant, also known as BRCA2 c.4215A>T by alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg1329Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Arg1329Ser occurs at a position that is not conserved across species and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Arg1329Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466166	SCV000549769	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166638	SCV000688842	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 1329 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 has reported that this variant does not impact BRCA2 function as assayed by response to PARP inhibitors (PMID: 32444794). This variant has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002996). This variant has been identified in 1/227200 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166638	SCV003848585	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).
PreventionGenetics, part of Exact Sciences	RCV004535127	SCV004121222	uncertain significance	BRCA2-related disorder	2023-04-20	criteria provided, single submitter	clinical testing	The BRCA2 c.3987A>T variant is predicted to result in the amino acid substitution p.Arg1329Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00094% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912479-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003995521	SCV004845253	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 1329 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 has reported that this variant does not impact BRCA2 function as assayed by response to PARP inhibitors (PMID: 32444794). This variant has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002996). This variant has been identified in 1/227200 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.