13-32326569-G-T

Variant names:

• chr13-32326569-G-T
• rs80358818
• NM_000059.4:c.587G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000059.4(BRCA2):​c.587G>T​(p.Ser196Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 6.72

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.587G>T	p.Ser196Ile	missense_variant	Exon 7 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.587G>T	p.Ser196Ile	missense_variant	Exon 7 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.218G>T	p.Ser73Ile	missense_variant	Exon 7 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.587G>T		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000278 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4

Jun 13, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 20, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

May 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 16, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

not specified Uncertain:1

Nov 27, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Fanconi anemia complementation group D1 Uncertain:1

Jun 13, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Uncertain:1

Oct 27, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.49
MutPred		0.26		Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);
MVP		0.91
MPC		0.17
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80358818; hg19: chr13-32900706; COSMIC: COSV66461606;