13-32363259-T-C

Variant names:

• chr13-32363259-T-C
• rs28897746
• NM_000059.4:c.8057T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8057T>C​(p.Leu2686Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2686V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.61
• Publications: 19 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 13-32363259-T-C is Pathogenic according to our data. Variant chr13-32363259-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8057T>C	p.Leu2686Pro	missense_variant	Exon 18 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8057T>C	p.Leu2686Pro	missense_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7688T>C	p.Leu2563Pro	missense_variant	Exon 18 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*115T>C		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*115T>C		3_prime_UTR_variant	Exon 17 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000141 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 05, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.8057T>C (p.Leu2686Pro) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) 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 251264 control chromosomes. c.8057T>C has been reported in the literature in one individual affected with Fanconi Anemia and a biallelic BRCA2 genotype (BRCA2 c.9672dupA (paternal) and c.8057T>C (maternal) (Dodgshun_2016). It was also identified in a proband from a family with Hereditary Breast And Ovarian Cancer (Azzollini_2016). At-least two multifactorial probability based assessments have classified this variant with a high probability of pathogenicity (example, Karchin_2008, Lindor_2012). Several publications report consistent experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Hart_2019). The most pronounced variant effect results in defective homology directed repair. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2686 of the BRCA2 protein (p.Leu2686Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 10923033, 26740091). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52489). Invitae Evidence Modeling incorporating data from in vitro 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: 29394989, 29988080). For these reasons, this variant has been classified as Pathogenic. -

Oct 10, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.2) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.994 and an overall classification of pathogenic. (PS3_strong). There are two likely pathogenic classifications on ClinVar for this variant from accredited USA diagnostic laboratories (Ambry Genetics and GeneDx, 2016) (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (1), UMD (5), BIC (1), and BRCA2 LOVD (1). -

not provided Pathogenic:2

May 19, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8285T>C. This variant was observed in an individual diagnosed with Fanconi Anemia who also harbored a pathogenic variant in trans with BRCA2 Leu2686Pro (Dodgshun 2016). This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA2 Leu2686Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2686Pro occurs at a position that is conserved across species and is located in the DNA binding domain, the nuclear export signal motif, and the SHFM1 binding domain (Marston 1999, Yang 2002, Jayesekharan 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2686Pro to be a likely pathogenic variant. -

Dec 10, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L2686P pathogenic mutation (also known as c.8057T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8057. The leucine at codon 2686 is replaced by proline, an amino acid with similar properties. This variant was detected in trans with a pathogenic BRCA2 mutation in a patient diagnosed with Fanconi Anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ. Cancer Genet. 2016;209:53-6). This alteration was defective in homology-directed DNA repair (HDR) assays, as well as a mouse ES cell growth assay (Hu C et al. Am J Hum Genet, 2024 Mar;111:584-593; Mesman RLS et al. Genet. Med. 2019 02;21:293-302). In addition, in a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 alteration is interpreted as a disease-causing mutation. -

Oct 08, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 2686 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant is deficient in the complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 29988080). This variant has been reported with a pathogenic BRCA2 co-variant in an individual affected with Fanconi anemia with a family history of cancer (PMID: 26740091). This variant was also included in multifactorial analysis studies with discordant reports of pathogenicity (PMID: 21990134, 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.55	D
PhyloP100		7.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.96
MutPred		0.76		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.97
MPC		0.19
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.92
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs28897746; hg19: chr13-32937396;