chr13-32338746-C-G

Variant names:

• chr13-32338746-C-G
• rs587776464
• NM_000059.4:c.4391C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.4391C>G​(p.Ser1464Cys) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1464A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.970
• Publications: 4 publications found

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]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21452948).
• BP6: Variant 13-32338746-C-G is Benign according to our data. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838. Variant chr13-32338746-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 856838.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4391C>G	p.Ser1464Cys	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.4391C>G	p.Ser1464Cys	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4022C>G	p.Ser1341Cys	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4391C>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Nov 22, 2022

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 cysteine at codon 1464 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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. -

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). -

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1464C variant (also known as c.4391C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 4391. The serine at codon 1464 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

May 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA2-related conditions. This sequence change replaces serine with cysteine at codon 1464 of the BRCA2 protein (p.Ser1464Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.92	T
PhyloP100		0.97
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.12
Sift	Benign	0.049	D;D
Sift4G	Benign	0.20	T;T
Vest4		0.41
MutPred		0.27		Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);
MVP		0.88
MPC		0.051
ClinPred		0.18	T
GERP RS		3.5
gMVP		0.52
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs587776464; hg19: chr13-32912883;