rs80358966

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2483N) has been classified as Likely benign.

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:12

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/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7447A>G	p.Ser2483Gly	missense_variant	15/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7447A>G	p.Ser2483Gly	missense_variant	15/27	5	NM_000059.4	A2

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2023	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 (Biswas et al., 2020); Published splicing studies demonstrate this variant results in slightly disrupted splicing with the majority of transcripts being full-length while only a minority of transcripts lacked the first 12 nucleotides of exon 15 (Fraile-Bethencourt et al., 2019; Montalban et al., 2019); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7675A>G; This variant is associated with the following publications: (PMID: 19043619, 21523855, 11979449, 12955716, 16685647, 26913838, 31191615, 12228710, 30472649, 32522261, 31396961, 21735045, 31343793, 33293522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 14, 2023	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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 23, 2022	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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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; Invitae). 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. -
Uncertain significance, no assertion criteria provided	research	Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	Mar 01, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 27, 2022

Variant summary: BRCA2 c.7447A>G (p.Ser2483Gly) results in a non-conservative amino acid change in 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 07, 2023

- -

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

MutationTaster

Benign

1.0

N;N

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