rs80359021

Variant names:

• chr13-32362657-T-C
• rs80359021
• NM_000059.4:c.7940T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 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. L2647V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:2
• Conservation: PhyloP100: 7.93
• Publications: 24 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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 15 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7940T>C	p.Leu2647Pro	missense_variant	Exon 17 of 27	ENST00000380152.8	NP_000050.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7940T>C (p.Leu2647Pro) variant has been reported in the published literature in affected individuals/families with breast and/or ovarian cancer (PMIDs: 18451181 (2008), 23108138 (2013), and 25447315 (2014)). It was also reported in an affected individual with breast cancer in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (BRCA2)). Functional studies demonstrated that this variant is damaging to protein function (PMIDs: 18451181 (2008), 23108138 (2013), 24323938 (2014), 29394989 (2018), 29884841 (2019), 29988080 (2018), 33609447 (2021), and 35736817 (2022)). In addition, multifactorial likelihood analyses have shown that this variant is likely to be associated with disease (PMIDs: 18451181 (2008), 19043619 (2008), 21990134 (2012), and 23108138 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 17, 2024

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 2647 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant impaired BRCA2 function in homology-directed repair assays (PMID: 23108138, 29394989, 30696104, 33609447, 35449176) and complementation of growth and PARP inhibitor sensitivity assays in Brca2-deficient mouse embryonic stem cells (PMID: 29988080, 32444794). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 18451181, 27062684). It also has been reported to segregate with disease (ClinVar accession: SCV000212960.8). 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. -

BRCA2-related disorder Pathogenic:1

Sep 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 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
PhyloP100		7.9
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
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: rs80359021; hg19: chr13-32936794;