Genetic Variant BRCA2:p.Ser2372* (chr13-32354968-C-G) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 3.50

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 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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7115C>G	p.Ser2372*	stop_gained	Exon 14 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7115C>G	p.Ser2372*	stop_gained	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.6746C>G	p.Ser2249*	stop_gained	Exon 14 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7115C>G		non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

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:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Mar 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7115C>G (p.Ser2372*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an individual affected with cell carcinomas of pancreas (PMID: 25743105 (2015)). The frequency of this variant in the general population, 0.000032 (1/31408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Mar 20, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 05, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder

Pathogenic:1

Jun 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 10, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast

Pathogenic:1

Apr 14, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Jan 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

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

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