NM_000059.4:c.3785C>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000059.4(BRCA2):c.3785C>G(p.Ser1262*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,602,446 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S1262S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17U:1O:1

Conservation

PhyloP100: 0.284

Publications

13 publications found

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 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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 13-32338140-C-G is Pathogenic according to our data. Variant chr13-32338140-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 51525.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.3785C>G	p.Ser1262*	stop_gained	Exon 11 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.3785C>G	p.Ser1262*	stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.3416C>G	p.Ser1139*	stop_gained	Exon 11 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.3785C>G		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242678

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000621

AC:

AN:

1450408

Hom.:

Cov.:

AF XY:

0.00000832

AC XY:

AN XY:

720832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33072

American (AMR)

AF:

0.00

AC:

AN:

43394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.00

AC:

AN:

83982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000814

AC:

AN:

1105738

Other (OTH)

AF:

0.00

AC:

AN:

60006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41380

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:6

Apr 02, 2018

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

- -

Apr 22, 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. -

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 23, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 30, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Apr 09, 2018

True Health Diagnostics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 26, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1262* pathogenic mutation (also known as c.3785C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3785. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been reported in numerous breast and/or ovarian cancer families (de Juan Jiménez I et al. Fam. Cancer 2013 Dec; 12(4):767-77; Song H et al. Hum. Mol. Genet. 2014 Sep; 23(17):4703-9; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). 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. -

Jul 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 5 individuals affected with breast or ovarian cancer (PMID: 18446624, 24728189, 31451522, 33471991, https://doi.org/10.3390/ijms241411570) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/242678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser1262X variant in BRCA2 has been reported in at least 6 individuals with BRCA2-related cancers (Song 2014, de Juan Jimenez 2013, Loughrey 2008, BIC database). It has also been identified in 1/110430 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant leads to a premature termination codon at position 1262, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51525). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -

Jan 22, 2025

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.Ser1262*) 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). This variant is present in population databases (rs80358620, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 24728189). ClinVar contains an entry for this variant (Variation ID: 51525). For these reasons, this variant has been classified as Pathogenic. -

Sep 03, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.3785C>G (p.Ser1262X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 245754 control chromosomes (gnomAD and publication data). c.3785C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Coulet_2010, Song_2014, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014), including one expert panel (ENIGMA), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 04, 2024

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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 18446624, 23479189, 24728189); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 4013C>G; This variant is associated with the following publications: (PMID: 20858050, 18446624, 28127413, 21702907, 24728189, 25525159, 26546047, 23479189, 29446198, 30720243, 30787465, 33087929, 29922827, 28888541, 34308104) -

Mar 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.3785C>G (p.(Ser1262*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 32073954 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)) and ovarian cancer (PMID: 24728189 (2014)). This variant has also been identified in a pediatric case of kidney cancer (PMID: 34308104 (2021)). The frequency of this variant in the general population, 0.0000041 (1/242678 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inherited ovarian cancer (without breast cancer)

Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Pathogenic:1

Feb 19, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA2-related disorder

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 09-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.27

Eigen_PC

Benign

-0.064

FATHMM_MKL

Benign

0.14

PhyloP100

0.28

Vest4

0.85

GERP RS

0.40

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over