13-32357808-T-C
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F2562V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | MANE Select | c.7684T>C | p.Phe2562Leu | missense | Exon 16 of 27 | NP_000050.3 | ||
| BRCA2 | NM_001432077.1 | c.7684T>C | p.Phe2562Leu | missense | Exon 16 of 27 | NP_001419006.1 | |||
| BRCA2 | NM_001406720.1 | c.7684T>C | p.Phe2562Leu | missense | Exon 16 of 27 | NP_001393649.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | TSL:5 MANE Select | c.7684T>C | p.Phe2562Leu | missense | Exon 16 of 27 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000544455.6 | TSL:1 | c.7684T>C | p.Phe2562Leu | missense | Exon 16 of 27 | ENSP00000439902.1 | ||
| BRCA2 | ENST00000530893.7 | TSL:1 | c.7315T>C | p.Phe2439Leu | missense | Exon 16 of 27 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461622Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727138 show subpopulations
Age Distribution
GnomAD4 genome 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4Benign:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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.
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.
not provided Pathogenic:1Uncertain:2
Identified in at least one family with breast and/or ovarian cancer (PMID: 27062684); Published functional studies demonstrate defective or intermediate impact on homology-directed repair (HDR) activity, inability to rescue cell lethality in a null cell line, and reduced binding to DSS1 (PMID: 29394989, 30696104, 29884841, 33293522, 35665744, 39779857, 39779848); 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, 25583207, 29394989, 27062684, 12228710, 39779848, 39779857, 33293522)
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 breast ovarian cancer syndrome Uncertain:3
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).
This classification follows the ClinGen ENIGMA BRCA2 v1.1.0 classification scheme; We chose this criterion: PS3 (strong pathogenic): 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).
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.
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
The c.7684T>C (p.F2562L) alteration is located in exon 16 (coding exon 15) of the BRCA2 gene. This alteration results from a T to C substitution at nucleotide position 7684, causing the phenylalanine (F) at amino acid position 2562 to be replaced by a leucine (L). Alternate variant conclusion statement: Based on the available evidence, the BRCA2 c.7684T>C (p.F2562L) alteration is classified as likely 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. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, 2015). In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in 1 family (Azzollini, 2016). This amino acid position is highly conserved in available vertebrate species. One homology directed repair (HDR) assay found this alteration to be defective (Guidugli, 2018), while another HDR assay found this alteration to have intermediate function (Hart, 2019). 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, 2025; Sahu, 2025). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
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.
not specified Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at