NM_000059.4:c.4637T>G

Variant names:

• chr13-32338992-T-G
• rs397507337
• NM_000059.4:c.4637T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000059.4(BRCA2):​c.4637T>G​(p.Phe1546Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. F1546L) 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:1 B:1
• Conservation: PhyloP100: 6.28
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32338992-T-G is Benign according to our data. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211. Variant chr13-32338992-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 924211.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4637T>G	p.Phe1546Cys	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.4637T>G	p.Phe1546Cys	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4268T>G	p.Phe1423Cys	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4637T>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 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). -

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with cysteine at codon 1546 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.50	D
PhyloP100		6.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.66
MutPred		0.54		Loss of stability (P = 0.031);Loss of stability (P = 0.031);
MVP		0.91
MPC		0.18
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.57
Mutation Taster		=52/48	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: rs397507337; hg19: chr13-32913129;