13-32354968-C-G

Position:

• chr13-32354968-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7115C>G​(p.Ser2372*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 3.50

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32354968-C-G is Pathogenic according to our data. Variant chr13-32354968-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 52271.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32354968-C-G is described in Lovd as [Pathogenic]. Variant chr13-32354968-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7115C>G	p.Ser2372*	stop_gained	14/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7115C>G	p.Ser2372*	stop_gained	14/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6746C>G	p.Ser2249*	stop_gained	14/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7115C>G		non_coding_transcript_exon_variant	13/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ser2372* variant was identified in 1 of 22 proband chromosomes (frequency: 0.05) from individuals or families with acinar cell carcinomas of the pancreas (Furukawa 2015). The variant was also identified in dbSNP (rs80358943) as “With pathogenic allele”, ClinVar (classified as pathogenic by Enigma, GeneDx, BIC, and CIMBA), LOVD 3.0 (2x), UMD-LSDB (6x as causal), and BIC (1x clinically important). The variant was not identified in COGR, Cosmic, ARUP Laboratories, or the Zhejiang University database. The variant was identified in control databases in 1 of 30980 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 8736 chromosomes (freq: 0.0001), but not in the European, South Asian, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser2372* variant leads to a premature stop codon at position 2372, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in individuals with BRCA2-related cancers (Furukawa et al., 2015; Palmer et al., 2020; Lerner-Ellis et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7343C>G; This variant is associated with the following publications: (PMID: 25743105, 31002019, 32377563, 32885271, 29446198, 32427313) -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The BRCA2 c.7115C>G variant is predicted to result in premature protein termination (p.Ser2372*). This variant has been reported in individuals with acinar cell carcinoma of the pancreas (Furukawa et al 2015. PubMed ID: 25743105) and breast cancer (Rebbeck TR et al 2018. PubMed ID: 29446198; Palmer JR et al 2020. PubMed ID: 32427313; Lerner-Ellis J et al 2020. PubMed ID: 32885271). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD; however, quality metrics indicate frequency data may not be reliable for this region (http://gnomad.broadinstitute.org/variant/13-32929105-C-G). Nonsense variants in BRCA2 are expected to be pathogenic, and several labs have classified this variant as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52271/). This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 14, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2019

The p.S2372* pathogenic mutation (also known as c.7115C>G), located in coding exon 13 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7115. This changes the amino acid from a serine to a stop codon within coding exon 13. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620). This alteration has also been reported in an individual with pancreatic acinar cell cancer (Furukawa T et al. Sci Rep, 2015 Mar;5:8829). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

This sequence change creates a premature translational stop signal (p.Ser2372*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with pancreatic cancer and increased risk of breast and/or ovarian cancer (PMID: 25743105, 29446198). ClinVar contains an entry for this variant (Variation ID: 52271). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.88
GERP RS		5.9

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: rs80358943; hg19: chr13-32929105; COSMIC: COSV101204598;