rs80359045

Positions:

chr13-32363265-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000059.4(BRCA2):c.8063T>C(p.Leu2688Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,060 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:2

Conservation

PhyloP100: 7.61

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 13-32363265-T-C is Pathogenic according to our data. Variant chr13-32363265-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8063T>C	p.Leu2688Pro	missense_variant	18/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8063T>C	p.Leu2688Pro	missense_variant	18/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7694T>C	p.Leu2565Pro	missense_variant	18/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*121T>C		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*121T>C		3_prime_UTR_variant	17/25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2020	Variant summary: BRCA2 c.8063T>C (p.Leu2688Pro) 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 251256 control chromosomes. c.8063T>C has been reported in the literature in individuals from at-least one family affected with Hereditary Breast And Ovarian Cancer although the exact number of case counts have not been specified (example, Guidugli_2013). These data do not allow any conclusion about variant significance. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of ability of BRCA2 to interact with the small (70-residues) DSS1 peptide, which appears to be crucial for the maintenance of its stability and correct conformation for the repair of DNA double stranded breaks (DSB's) by homologous recombination (HR) and the formation of DNA damage induced RAD51 foci (Caleca_2019). Consistently, other studies report a corresponding loss of HDR activity (example, Guidugli_2013 and Hart_2019). Five 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 pathogenic (n=1)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2688 of the BRCA2 protein (p.Leu2688Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 38137). 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: 23108138, 29394989, 30696104, 32444794, 33609447, 33964450). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 31, 2018	Data used in classification. The variant was observed in 2 independent UK families undergoing clinical diagnostic testing of BRCA1/BRCA2 for HBOC, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) 2-sided Fishers exact: pexact= 0.043 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals). (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Segregation demonstrated in one UK family, N<1/16 (PP1_mod). P>0.99 on HR assay as detailed in Guidugli et al 2012 (Couch laboratory), which has demonstrated full validation against genetic epidemiological data of clinical pathogicity (PS3). Classified as pathogenic by Ambry and Quest Diagnostics (PP5). Data not used in classification. An additional 2 families have been identified in the UK (not included in the previous dataset).There are 5 additional reports of this variant on ClinVar. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2020	In the published literature, the variant has been reported to be defective in homology-directed DNA repair (PMID: 23108138 (2013), 29394989 (2018)). Additionally, it did not complement mouse embryonic cell lines deficient in BRCA2 (PMID: 29988080 (2018)). Therefore, the variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	Published functional studies demonstrate a damaging effect: decreased homology-directed repair activity, protein binding, and sensitivity to PARP inhibitors (Guidugli 2013, Guidugli 2018, Mesman 2018, Caleca 2019, Hart 2019, Ikegami 2020, Richardson 2021); Multifactorial studies suggest this variant is likely associated with breast and ovarian cancer (Lindor 20012); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8291T>C; This variant is associated with the following publications: (PMID: 29884841, 23108138, 29394989, 29988080, 30696104, 32444794, 33609447, 21990134, 12228710, 32170000, 32042831, 31569370, 20167696, 19043619, 24323938) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2024	The p.L2688P pathogenic mutation (also known as c.8063T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8063. The leucine at codon 2688 is replaced by proline, an amino acid with similar properties. In one 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 deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This alteration has been predicted to be pathogenic using homology-directed DNA repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). This variant segregated with disease in multiple families (Ambry internal data). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 08, 2019	This missense variant replaces leucine with proline at codon 2688 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 homology-mediated DNA repair and the complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 23108138, 29988080). A multifactorial analysis reported family history odds of pathogenicity of 3.44 with posterior probability of pathogenicity of 0.95 (PMID: 23108138) and ClinVar report indicated the identification of this variant in affected pedigrees in the UK (RCV000045408.5). 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:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 15, 2006	- -

BRCA2-related cancer predisposition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 03, 2024

This missense variant replaces leucine with proline at codon 2688 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 homology-mediated DNA repair and the complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 23108138, 29988080). A multifactorial analysis reported family history odds of pathogenicity of 3.44 with posterior probability of pathogenicity of 0.95 (PMID: 23108138) and ClinVar report indicated the identification of this variant in affected pedigrees in the UK (RCV000045408.5). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.95

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.95

MutPred

0.82

Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);

MVP

0.99

MPC

0.19

ClinPred

1.0

GERP RS

5.1

gMVP

0.95

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

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

Other links and lift over