chr13-32357809-T-G

Variant names:

• chr13-32357809-T-G
• rs587782715
• NM_000059.4:c.7685T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000059.4(BRCA2):​c.7685T>G​(p.Phe2562Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 7.45

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 13-32357809-T-G is Pathogenic according to our data. Variant chr13-32357809-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142784.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7685T>G	p.Phe2562Cys	missense_variant	Exon 16 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7685T>G	p.Phe2562Cys	missense_variant	Exon 16 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7316T>G	p.Phe2439Cys	missense_variant	Exon 16 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7685T>G		non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Mar 02, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Published functional studies have shown that this variant has a deleterious effect on BRCA2 homology-directed DNA repair activity (PMIDs: 33609447 (2021) and 35736817 (2022)). Also, analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Nov 22, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32377563) -

BRCA2-related disorder Pathogenic:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.7685T>G variant is predicted to result in the amino acid substitution p.Phe2562Cys. To our knowledge, this variant has not been reported in the literature in individuals affected with BRCA2-related conditions. However, we have observed this variant in the homozygous state in a patient whose overall phenotypic presentation is consistent with Fanconi anemia (PreventionGenetics internal data). Chromosomal breakage studies performed for that patient and in vitro HDR repair assays reported in the literature have demonstrated that this variant negatively impacts BRCA2 function (Richardson et al. 2021. PubMed ID: 33609447; Hu et al. 2022. PubMed ID: 35736817; PreventionGenetics internal data). This variant has not been reported in the gnomAD database and has conflicting interpretations in ClinVar ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/142784/). Taken together, this variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F2562C pathogenic mutation (also known as c.7685T>G), located in coding exon 15 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7685. The phenylalanine at codon 2562 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been confirmed in trans with a BRCA2 pathogenic variant in an individual diagnosed with Fanconi anemia (Ambry internal data). This alteration was identified as non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet. 2021 03;108(3):458-468). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi anemia, it is likely to be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Sep 17, 2023

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 phenylalanine with cysteine at codon 2562 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found the variant protein to be defective in homology-directed DNA repair assays in mammalian cells (PMID: 33609447, 35736817). This variant has been observed in an individual affected with autosomal recessive Fanconi anemia in trans with a pathogenic BRCA2 variant (ClinVar: SCV000187274.8). 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. -

Familial cancer of breast Uncertain:1

Oct 17, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2562 of the BRCA2 protein (p.Phe2562Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142784). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447). 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	0.89
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.82
MutPred		0.87		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.98
MPC		0.18
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782715; hg19: chr13-32931946;