13-32357808-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000059.4(BRCA2):c.7684T>C(p.Phe2562Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:11B:1

Conservation

PhyloP100: 7.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7684T>C	p.Phe2562Leu	missense_variant	Exon 16 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7684T>C	p.Phe2562Leu	missense_variant	Exon 16 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7315T>C	p.Phe2439Leu	missense_variant	Exon 16 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7684T>C		non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727138

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000507

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4Benign:1

Apr 09, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7684T>C (p.Phe2562Leu) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function. In published homology-directed repair assays, this variant was found to have an intermediate (PMID: 29884841) and deleterious (PMID: 29394989) impact on protein function. This variant has been reported in conjunction with a pathogenic BRCA2 variant in a cell line derived from an individual with Faconi anemia, however the phase was not described (PMID: 25583207). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Oct 06, 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 leucine 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 shown that this variant to be defective in a homology-directed DNA repair assay (PMID: 29394989, 30696104). This variant has been reported in an individual at risk for hereditary breast and ovarian cancer (PMID: 27062684). This variant also has been reported with a pathogenic BRCA2 covariant in a cell line from an individual affected with Fanconi anemia, although the phasing of the two variants is unknown (PMID: 25583207). 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. -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 27, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:2

Aug 26, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate defective or intermediate impact on homology-directed repair (HDR) activity and reduced binding to DSS1 (PMID: 29394989, 30696104, 29884841, 35665744); Identified in at least one family with breast and/or ovarian cancer (PMID: 27062684); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7912T>C; This variant is associated with the following publications: (PMID: 19043619, 17452773, 25348012, 30696104, 29884841, 35665744, 29394989, 12228710, 27062684, 25583207) -

Feb 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7684T>C; p.Phe2562Leu variant (rs80358995) is reported in the literature in an individual affected with breast and/or ovarian cancer (Azzollini 2016), and in an individual affected with Fanconi anemia who also has a pathogenic frameshift variant in BRCA2, although the phase is unknown (Stoepker 2015). In vitro functional analyses demonstrate reduced homology directed repair activity (Biswas 2020, Caleca 2019, Guidugli 2018). This variant is also reported in ClinVar (Variation ID: 38114), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are not informative (BayesDel 0.288). Given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Azzollini J et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. PMID: 27062684. Biswas K et al. A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. NPJ Genom Med. 2020 Dec 8;5(1):52. PMID: 33293522. Caleca L et al. GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the BRCA1 and BRCA2 Genes. Cancers (Basel). 2019 Jan 28;11(2):151. PMID: 30696104. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. PMID: 29394989. Stoepker C et al. DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity. DNA Repair (Amst). 2015 Feb;26:54-64. PMID: 25583207. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Sep 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 26, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F2562L variant (also known as c.7684T>C), located in coding exon 15 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7684. The phenylalanine at codon 2562 is replaced by leucine, an amino acid with highly similar properties. This alteration co-occurs with a pathogenic BRCA2 frameshift mutation in a cell line derived from a Fanconi Anemia patient; however, the phase of these two alterations was not described (Stoepker C et al. DNA Repair (Amst.), 2015 Feb;26:54-64). One homology directed repair (HDR) assay found this alteration to be defective (Guidugli L et al. Am. J. Hum. Genet., 2018 Jan;:), while another HDR assay found this alteration to have intermediate function (Hart SN et al. Genet Med, 2019 01;21:71-80). Two saturation genome editing-based studies, including a haploid cell-survival assay and a humanized mouse embryonic stem cell line assay of drug response and survival, demonstrate that this nucleotide substitution may be non-functional (Huang H et al. Nature. 2025 Feb;638(8050):528-537; Sahu S et al. Nature. 2025 Feb;638(8050):538-545). In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71).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 majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it may 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Jan 30, 2025

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 leucine, which is neutral and non-polar, at codon 2562 of the BRCA2 protein (p.Phe2562Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, Fanconi anemia, and/or ovarian cancer (PMID: 25583207, 27062684). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with features of Fanconi anemia (external communication). However, this variant has also been observed as homozygous in an adult individual with breast cancer, but without other Fanconi anemia features (internal data). ClinVar contains an entry for this variant (Variation ID: 38114). 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%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 30696104). 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. -

Dec 11, 2023

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Data used in classification: The frequency of this variant is 0/138,632 individuals in gnomAD (PM2_mod). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). December 2023 Update: Functional assay data has since been made available (Hart et al., 2019, PMID: 29884841) which supersedes the previously applied Guidugli et al., 2018 assay results. The new data shows an intermediate result, therefore, this functional assay data is no longer applicable towards pathogenicity. Data not used in classification: There are conflicting in silico predictions; AlignGVGD (class: C15), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (27.2). -

not specified

Uncertain:1

Oct 16, 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.7684T>C (p.Phe2562Leu) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251286 control chromosomes. c.7684T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or Fanconi Anemia (Stoepker_2015, Azzollini_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant decreased the BRCA2 function (Guidugli_2018, Hart_2019, Caleca_2019, Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 33293522, 30696104, 29394989, 29884841, 25583207). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS n=6, likely pathogenic n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

BRCA2-related disorder

Uncertain:1

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.7684T>C variant is predicted to result in the amino acid substitution p.Phe2562Leu. This variant has been reported in an individual with hereditary breast and/or ovarian cancer (Azzollini et al. 2016. PubMed ID: 27062684). It has also been reported along with a second pathogenic variant in a lymphoblastoid cell line in an individual with Fanconi anemia; however confirmation of phase of the two variants was not determined (Stoepker et al. 2014. PubMed ID: 25583207). Functional studies report conflicting results in that some indicate a detrimental effect on protein function and viability (Biswas et al. 2020. PubMed ID: 33293522; Caleca et al. 2019. PubMed ID: 30696104), where other studies suggest a neutral or intermediate effect on protein function (Hart et al. 2018. PubMed ID: 29884841; Karchin et al. 2008. PubMed ID: 19043619). This variant is not present in a large population database, indicating this is rare. It has conflicting classifications in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/38114/). An alternate nucleotide change affecting the same amino acid has been reported in an individual with clinical features consistent with Fanconi anemia (Internal Data, PreventionGenetics). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.78

MutPred

0.88

Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);

MVP

0.97

MPC

0.17

ClinPred

1.0

GERP RS

5.2

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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