13-32337561-C-T

Variant names:

• chr13-32337561-C-T
• rs80358563
• NM_000059.4:c.3206C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000059.4(BRCA2):​c.3206C>T​(p.Ser1069Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 2.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39846936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3206C>T	p.Ser1069Phe	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3206C>T	p.Ser1069Phe	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2837C>T	p.Ser946Phe	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3206C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454796 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 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 phenylalanine at codon 1069 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). Functional studies have shown that this variant impairs APRIN interaction and can partially rescue homology-directed DNA repair deficiency (PMID: 22293751). This variant has been reported in 1 individual affected with breast cancer, this individual also carried a pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 25186627). This variant has not been identified 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. -

May 08, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1069F variant (also known as c.3206C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3206. The serine at codon 1069 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is 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. -

Jun 13, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:2

Mar 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). It has also been reported in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), ). One functional study demonstrated that this variant may prevent BRCA2 homology-directed repair (PMID: 22293751 (2012)), but additional functional studies are needed to determine the overall impact of this variant on gene and gene product. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3434C>T; This variant is associated with the following publications: (PMID: 31131967, 25186627, 33471991, 22293751, 37922907) -

not specified Uncertain:1

Nov 13, 2023

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.3206C>T (p.Ser1069Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245554 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3206C>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with Breast/Ovarian cancer (example, Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two co-occurrences with another pathogenic variant have been reported (BRCA2 c.5042_5043delTG, p.Val1681Glufs*7; Tung_2014 and internal sample), providing supporting evidence for a benign role. One publication reports experimental evidence that the variant reduces association with APRIN (Brough_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22293751, 25186627). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=1 VUS, n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

BRCA2-related disorder Uncertain:1

Feb 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.3206C>T variant is predicted to result in the amino acid substitution p.Ser1069Phe. This variant has been reported in a patient with breast cancer that also had a different BRCA2 pathogenic variant (Tung et al. 2014. PubMed ID: 25186627). This variant was found in one control individual (Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). In a multifactorial likelihood analysis, this variant was reported to have uncertain significance for cancer susceptibility (Parsons et al. 2019. PubMed ID: 31131967). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to missense variation (Dines et al. 2020. PubMed ID: 31911673). In vitro experimental studies suggest this variant impairs BRCA2/ARPIN interaction and homologous recombination, but did not impact BRCA2/RAD51 interaction (Brough et al. 2012. PubMed ID: 22293751). This variant has not been reported in a large population database, indicating this variant is rare. It has conflicting classifications listed in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/51423/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Dec 08, 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 phenylalanine, which is neutral and non-polar, at codon 1069 of the BRCA2 protein (p.Ser1069Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 51423). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	Benign	0.18
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.064
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.48	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Vest4		0.42
MutPred		0.40		Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);
MVP		0.90
MPC		0.056
ClinPred		0.99	D
GERP RS		4.6
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80358563; hg19: chr13-32911698;