Submissions for variant NM_000059.4(BRCA2):c.587G>T (p.Ser196Ile)

dbSNP: rs80358818

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044783	SCV000072796	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 196 of the BRCA2 protein (p.Ser196Ile). This variant is present in population databases (rs80358818, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21218378, 30287823). ClinVar contains an entry for this variant (Variation ID: 51959). 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 with a negative predictive value of 95%. 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	RCV000166163	SCV000216937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	The p.S196I variant (also known as c.587G>T), located in coding exon 6 of the BRCA2 gene, results from a G to T substitution at nucleotide position 587. The serine at codon 196 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was observed with an allele frequency of 0.00028 in 7051 unselected female breast cancer patients and was observed with an allele frequency of 0.00027 in 11241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.006 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also observed in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This alteration was shown to cause slightly increased exon skipping in splicing mini gene assays (Gaildrat P et al. J Med Genet, 2012 Oct;49:609-17; Di Giacomo D et al. Hum Mutat. 2013 Nov;34(11):1547-57). This amino acid position is highly 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.
Counsyl	RCV000113840	SCV000489341	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780031	SCV000917037	uncertain significance	not specified	2019-11-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.587G>T (p.Ser196Ile) 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 4e-06 in 251402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. The variant, c.587G>T, has been reported in the literature in several individuals of Japanese ancestry, and was found in both patients affected with breast cancer, and healthy controls (Momozawa 2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact exon 7 skipping, however, does not allow convincing conclusions about the variant effect (Di Giacomo_2013). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000113840	SCV001269107	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-13	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001111542	SCV001269108	uncertain significance	Fanconi anemia complementation group D1	2017-06-13	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV003441732	SCV004170558	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Identified in individuals with breast cancer as well as unaffected controls (PMID: 21218378, 30287823); Published functional studies demonstrate disrupted phosphorylation and binding of TGFBR2 and ACVR2B at the Ser193 position (PMID: 23704879); Published functional studies demonstrate aberrant splicing in a minority of transcripts (PMID: 23983145); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 815G>T; This variant is associated with the following publications: (PMID: 10923033, 23704879, 21218378, 26761715, 30287823, 29192238, 32377563, 29884841, 33428613, 35373174, 23983145)
Color Diagnostics, LLC DBA Color Health	RCV000166163	SCV004361181	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 196 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). This variant alters a serine residue that is thought to be involved in BRCA2 interaction with p300/CBP-associated factor (PMID: 12815053, 23704879). Mini-gene assays have reported that this variant causes skipping of exon 7, but over 70% of the transcripts retained exon 7 (PMID: 22962691, 26761715). This variant has shown insignificant association with female breast cancer in a large Japanese case-control study (2/705 cases and 3/11241 controls, OR=1.06, 95% CI 0.1-9.3; PMID 30287823). This variant has been identified in 1/251402 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.
All of Us Research Program, National Institutes of Health	RCV000113840	SCV004846792	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 196 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). This variant alters a serine residue that is thought to be involved in BRCA2 interaction with p300/CBP-associated factor (PMID: 12815053, 23704879). Mini-gene assays have reported that this variant causes skipping of exon 7, but over 70% of the transcripts retained exon 7 (PMID: 22962691, 26761715). This variant has shown insignificant association with female breast cancer in a large Japanese case-control study (2/705 cases and 3/11241 controls, OR=1.06, 95% CI 0.1-9.3; PMID 30287823). This variant has been identified in 1/251402 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113840	SCV000147221	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing