rs80359021

Positions:

• chr13-32362657-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7940T>C​(p.Leu2647Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L2647?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:2
• Conservation: PhyloP100: 7.93

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32362656-CTA-CC is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 13-32362657-T-C is Pathogenic according to our data. Variant chr13-32362657-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32362657-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7940T>C	p.Leu2647Pro	missense_variant	17/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7940T>C	p.Leu2647Pro	missense_variant	17/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7571T>C	p.Leu2524Pro	missense_variant	17/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7948T>C		non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1 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)	Sep 30, 2010	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	Published functional studies demonstrate a damaging effect: reduced homology-directed repair activity and aberrant centriole amplification (Farrugia et al., 2008; Guidugli et al., 2018; Hart et al., 2019; Richardson et al., 2021); Observed in individuals with breast, ovarian, or prostate cancer (Farrugia et al., 2008; Azzollini et al., 2016; Secondino et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8168T>C; This variant is associated with the following publications: (PMID: 19043619, 25447315, 28339459, 23108138, 24323938, 21990165, 21990134, 29394989, 29988080, 32444794, 30696104, 29969168, 28866612, 28277317, 29884841, 12228710, 34906479, 35456488, 18451181, 33609447, 27062684, 33964450) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2020	This missense variant replaces leucine with proline at codon 2647 in the DNA binding/OB tower domain 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). Multiple functional studies have shown that this variant impairs BRCA1 protein function (PMID: 18451181, 23108138, 24323938, 29394989, 29988080, 30696104, Ikegami 2020). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 18451181, 27062684). Multifactorial likelihood analyses have shown that this variant is likely associated with disease (PMID: PMID: 18451181, 21990134, 23108138). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2023	The p.L2647P pathogenic mutation (also known as c.7940T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7940. The leucine at codon 2647 is replaced by proline, an amino acid with similar properties. Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). In functional studies, this alteration has displayed reduced homology-directed DNA repair (HDR) and induced at least a 2-fold increase in the proportion of cells undergoing aberrant centriole amplification (Farrugia DJ, Cancer Res. 2008 May; 68:3523-31; 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. -

BRCA2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2023

The BRCA2 c.7940T>C variant is predicted to result in the amino acid substitution p.Leu2647Pro. This variant has been reported in individuals with BRCA2-related cancers (Farrugia et al. 2008. PubMed ID: 18451181; Table S2, Azzollini et al. 2016. PubMed ID: 27062684; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541). Functional studies found this variant disrupts BRCA2 function (Farrugia et al. 2008. PubMed ID: 18451181; Guidugli et al. 2013. PubMed ID: 23108138; Table S1, Richardson et al. 2021. PubMed ID: 33609447). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/52443/). This variant is interpreted as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2647 of the BRCA2 protein (p.Leu2647Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 23108138, 25447315). ClinVar contains an entry for this variant (Variation ID: 52443). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 18451181, 23108138, 29884841, 29988080, 32444794, 33964450, 35736817). Studies have shown that this missense change does not affect mRNA splicing (PMID: 28339459, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.94
MutPred		0.86		Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);
MVP		0.98
MPC		0.19
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.82

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

Other links and lift over

dbSNP: rs80359021; hg19: chr13-32936794;