13-32357883-C-T

Position:

• chr13-32357883-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_000059.4(BRCA2):​c.7759C>T​(p.Leu2587Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,928 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). Synonymous variant affecting the same amino acid position (i.e. L2587L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:8
• Conservation: PhyloP100: 2.69

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• BP6: Variant 13-32357883-C-T is Benign according to our data. Variant chr13-32357883-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141335.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=7, Benign=1, Likely_pathogenic=1}. Variant chr13-32357883-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7759C>T	p.Leu2587Phe	missense_variant	16/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7759C>T	p.Leu2587Phe	missense_variant	16/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7390C>T	p.Leu2464Phe	missense_variant	16/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7759C>T		non_coding_transcript_exon_variant	15/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251436 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000594

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

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: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Jul 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2023	Variant summary: BRCA2 c.7759C>T (p.Leu2587Phe) 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 allele was found at a frequency of 4.4e-05 in 251514 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.7759C>T has been reported in the literature in individuals undergoing evaluation for breast/colorectal cancer (example, Velasco_2005, Garre_2014, Tsai_2019). Some of these reports classify the variant as a VUS within settings of multigene panel testing (example, Tsai_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported in the LOVD database (BRCA1 c.2197_2201delGAGAA, p.Glu733fsX5), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Richardson_2021, Hu_2022). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29849630, 27165003, 29881398, 24814045, 29394989, 29884841, 35736817, 16758124, 20167696, 33609447, 30374176, 15937982, 30055349). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: likely benign (n=3), benign (n=1), VUS, n=8 and likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 21, 2019	The BRCA2 c.7759C>T; p.Leu2587Phe variant (rs56335340), also known as 7987C>T, is reported in the literature in individuals affected with breast and/or ovarian cancer (Infante 2006, Velasco 2005, Zuntini 2018) and colorectal cancer (Esteban-Jurado 2016, Garre 2015). This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 141335), and is found in the general population with an overall allele frequency of 0.0044% (11/251436 alleles) in the Genome Aggregation Database. The leucine at codon 2587 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Leu2587Phe variant is uncertain at this time. References: Esteban-Jurado C et al. The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer. Eur J Hum Genet. 2016 Oct;24(10):1501-5. Garre P et al. BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet. 2015 Jun;87(6):582-7. Infante M et al. High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-Leon (central Spain). J Hum Genet. 2006;51(7):611-7. Velasco E et al. Rapid mutation detection in complex genes by heteroduplex analysis with capillary array electrophoresis. Electrophoresis. 2005 Jun;26(13):2539-52. Zuntini R et al. Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? Front Genet. 2018 Sep 11;9:378. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 25, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 10, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 06, 2018	- -

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

Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Supporting)+BS3(Strong)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	This variant is denoted BRCA2 c.7759C>T at the cDNA level, p.Leu2587Phe (L2587F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). Using alternate nomenclature, this variant would be defined as BRCA2 7987C>T. This variant was observed in several individuals with a personal and family history of colorectal cancer as well as two individuals with a personal and/or family history of breast and/or ovarian cancer (Infante 2006, Garre 2015, Esteban-Jurado 2016, Zutini 2018). BRCA2 Leu2587Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Leu2587Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 08, 2022	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2587 of the BRCA2 protein (p.Leu2587Phe). This variant is present in population databases (rs56335340, gnomAD 0.006%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 15937982, 16758124, 24814045, 30254663). This variant is also known as 7987C>T. ClinVar contains an entry for this variant (Variation ID: 141335). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29394989). 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. -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

Carcinoma of colon Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer

Nov 01, 2015

Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for gastric cancer -

BRCA2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

The BRCA2 c.7759C>T variant is predicted to result in the amino acid substitution p.Leu2587Phe. This variant has been reported in individuals with colorectal, breast, ovarian, and/or prostate cancer (Infante et al. 2006. PubMed ID: 16758124; Table 1, Garre et al. 2015. PubMed ID: 24814045; Figure S1a, Esteban-Jurado et al. 2016. PubMed ID: 27165003; Figure S1, Table S1, Family 1023, Tsai et al. 2018. PubMed ID: 30374176; Table S3, referred to as Chr13:32932020C>T, Darst et al. 2021. PubMed ID: 32853339). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to likely pathogenic, with the vast majority of clinical laboratory contributors interpreting it as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141335/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

BRCA2-related cancer predisposition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.93	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.68
MutPred		0.86		Loss of disorder (P = 0.2043);Loss of disorder (P = 0.2043);
MVP		0.97
MPC		0.17
ClinPred		0.63	D
GERP RS		5.2
gMVP		0.66

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: rs56335340; hg19: chr13-32932020;