rs80358966

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000059.4(BRCA2):c.7447A>G(p.Ser2483Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 2.01

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7447A>G	p.Ser2483Gly	missense_variant	Exon 15 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.7447A>G	p.Ser2483Gly	missense_variant	Exon 15 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7078A>G	p.Ser2360Gly	missense_variant	Exon 15 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7447A>G		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251306

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461254

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000478

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Mar 13, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used: PP3. -

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with glycine at codon 2483 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 02, 2020

BRCAlab, Lund University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:2

Jun 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer or Lynch syndrome (PMIDs: 11979449 (2002), 12955716 (2003), 16685647 (2006), 21735045 (2012), and 32522261 (2020)) and in an individual with Esophageal squamous carcinoma (PMID: 31396961 (2020)). Functional studies using cell survival and drug sensitivity assays showed that the variant is likely functional (PMID: 33293522 (2020)). In addition, other experimental studies reported that this variant resulted in only 10% of transcripts with an in-frame partial deletion of exon 15 while most of transcripts (90%) were full length (PMIDs: 31343793 (2019) and 31191615 (2019)). The frequency of this variant in the general population, 0.000087 (3/34572 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant results in cell survival similar to wild-type in assays evaluating ability to rescue BRCA2-null lethality and sensitivity to DNA damaging agents (PMID: 33293522); Published splicing studies demonstrate an incomplete splice impact, with the majority of transcripts being full-length while only a minority of transcripts lacked the first 12 nucleotides of exon 15 (PMID: 31343793, 31191615, 30472649); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7675A>G; This variant is associated with the following publications: (PMID: 19043619, 21523855, 11979449, 12955716, 16685647, 26913838, 31191615, 30472649, 21735045, 32522261, 31396961, 33471991, 12228710, 31343793, 33293522) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S2483G variant (also known as c.7447A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7447. The serine at codon 2483 is replaced by glycine, an amino acid with similar properties. This variant has been reported in high risk breast cancer families and a high risk breast and ovarian cancer family (Osorio A et al. Int. J. Cancer. 2002 May;99:305-9; Weber F et al. Am. J. Hum. Genet. 2006 Jun;78:961-72; Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12). One study found that this alteration results in incomplete use of this cryptic acceptor site, producing a transcript with the predicted in-frame deletion of 12 nucleotides in coding exon 14 (Fraile-Bethencourt E et al. Front Genet. 2019 May;10:503). However, other studies have found that this alteration does not result in a significant amount of aberrant splicing (Ambry internal data, Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92). This amino acid position is poorly conserved in available vertebrate species. In addition, this amino acid change is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jan 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome

Uncertain:2

Mar 01, 2019

Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2483 of the BRCA2 protein (p.Ser2483Gly). This variant is present in population databases (rs80358966, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, esophageal squamous cell carcinoma, and/or ovarian cancer (PMID: 11979449, 12955716, 21735045, 31396961). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31191615, 31343793; internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Nov 07, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.7447A>G (p.Ser2483Gly) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function.A computational method that produces a probabilistic likelihood ratio has predicted a neutral impact (Karchin_2008). 5/5 computational tools predict no significant impact on normal splicing at the canonical splice acceptor site although three tools predicted the creation of a new exonic acceptor site located 12 nucleotides downstream from the canonical splice acceptor site (Montalban_2019). At-least two studies reported a very low levels (10%) of transcript lacking 12 nucleotides from the 5' end of exon 15, while the majority of transcripts (90%) were full length (Montalban_2019, Fraile-Bethencourt_2019). However, the exact in-vivo consequences of these findings is not clear. The variant allele was found at a frequency of 1.6e-05 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7447A>G has been reported in the literature in individuals from a Spanish family affected with breast cancer (Osorio_2002) that has been subsequently cited by others (Diez_2003, Montalban_2019) and in one case from a study of Esophageal squamous carcinoma in China (Ko_2020). Tumor analysis performed in the initial report from the Spanish family demonstrated retention of the wild-type allele and loss of the allele harbouring the variant confirming that the variant is not deleterious (Osorio_2002). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2020). These results showed "no damaging effect" of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of BRCA2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. This finding is consistent with the predominantly wild-type transcript pattern in the splicing assays summarized above. The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 12955716, 31191615, 19043619, 31396961, 21735045, 31343793, 11979449, 32522261, 16685647). ClinVar contains an entry for this variant (Variation ID: 52334). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast

Uncertain:1

Mar 05, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.51

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.46

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.29

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.034

D;D

Vest4

0.25

MutPred

0.65

Loss of stability (P = 0.0593);Loss of stability (P = 0.0593);

MVP

0.83

MPC

0.026

ClinPred

0.12

GERP RS

1.7

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.51

Position offset: 1

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