Submissions for variant NM_000059.4(BRCA2):c.5644T>C (p.Ser1882Pro)

dbSNP: rs730881538

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590236	SCV000210358	uncertain significance	not provided	2016-05-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5644T>C at the cDNA level, p.Ser1882Pro (S1882P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 5872T>C. This variant has been observed in at least one individual from a hereditary breast and/or ovarian cancer family (van der Hout 2006). BRCA2 Ser1882Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1882Pro occurs at a position that is not conserved and is located in RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser1882Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000257958	SCV000324857	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590236	SCV000694887	uncertain significance	not provided	2017-06-08	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5644T>C (p.Ser1882Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120634 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in at least 1 HBOC family (van der Hout_HM_2006), but without strong evidence for pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as variant of uncertain significance. Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000772756	SCV000906113	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 1882 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 reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer and two unaffected individuals (PMID: 16683254, 33471991; Leiden Open Variation Database DB-ID BRCA2_001601). This variant has been identified in 1/249428 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.
Invitae	RCV000806443	SCV000946444	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1882 of the BRCA2 protein (p.Ser1882Pro). This variant is present in population databases (rs730881538, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16683254). ClinVar contains an entry for this variant (Variation ID: 182219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000772756	SCV001186362	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-05	criteria provided, single submitter	clinical testing	The p.S1882P variant (also known as c.5644T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 5644. The serine at codon 1882 is replaced by proline, an amino acid with similar properties. One study identified this alteration in 1/431 Dutch breast and/or ovarian cancer families (van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772756	SCV003848979	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).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590236	SCV001928009	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590236	SCV001959204	likely benign	not provided		no assertion criteria provided	clinical testing