rs80359082

Positions:

• chr13-32370447-G-A
• chr13-32370447-G-C
• chr13-32370447-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8377G>A​(p.Gly2793Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,688 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2793E?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 U:2
• Conservation: PhyloP100: 9.94

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32370447-GG-GAA is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 13-32370447-G-A is Pathogenic according to our data. Variant chr13-32370447-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32370447-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8377G>A	p.Gly2793Arg	missense_variant	19/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8377G>A	p.Gly2793Arg	missense_variant	19/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8008G>A	p.Gly2670Arg	missense_variant	19/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*435G>A		non_coding_transcript_exon_variant	18/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*435G>A		3_prime_UTR_variant	18/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4 Uncertain:1

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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 02, 2012	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 31, 2015	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change replaces Glycine for Arginine at codon 2793 of the BRCA2 protein. The glycine residue is highly conserved in a functional domain of the protein and there is a big physiochemical difference between glycine and arginine. This variant has been observed in 4 families affected with breast and/or ovarian cancer. Algorithms developed to predict the effect of missense changes on protein structure and functions suggest that this variant is likely to be detrimental to protein function. Experimental studies have shown that this missense change results in homology-directed repair activity comparable to known pathogenic mutations. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2019	PS3, PS4_Mod, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	Published functional studies demonstrate a damaging effect: significantly reduced homologous recombination DNA-repair activity and inability to rescue cell lethality in an embryonic stem cell assay (PMID: 23108138, 29394989, 29884841, 33293522, 33609447, 35736817, 35665744); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 8605G>A; This variant is associated with the following publications: (PMID: 15889636, 29446198, 24323938, 25085752, 23233716, 19043619, 25777348, 16030099, 12442275, 29394989, 29997359, 28127413, 29922827, 30630528, 31331294, 30728895, 30264118, 26580448, 33293522, 29884841, 33609447, 23108138, 30787465, 12228710, 35665744, 35736817) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2021	In the published literature, this variant has been identified in individuals with breast cancer and breast/ovarian cancer families (PMID: 12442275 (2002), 15889636 (2005), 23233716 (2013), 25777348 (2015), and 31331294 (2019)). In addition, functional studies have shown that this variant greatly reduces the homology-directed DNA repair (HDR) activity of the BRCA2 protein (PMID: 23108138 (2013)). Furthermore, a multifactorial study reports that this variant is strongly associated with disease in families with a history of breast cancer (PMID: 25085752 (2014)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	This missense variant replaces glycine with arginine at codon 2793 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant to impact BRCA2 function in homology-mediated repair assay and in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 23108138, 29394989, 33293522, 33609447, 35736817). This variant has been detected in at least five individuals affected with high-risk breast cancer (PMID: 12442275, 25777348, 31331294; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 16030099, 23233716). This variant has been identified in 2/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 22, 2021	The p.G2793R pathogenic mutation (also known as c.8377G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8377. The glycine at codon 2793 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the DNA binding domain (DBD) of BRCA2 and was classified as pathogenic (p ≥ 0.999) by a highly sensitive and specific model based on in vivo homology-directed repair (HDR) activity (Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75l; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan;). In addition, this alteration was predicted to be likely deleterious based on a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This alteration has been detected in multiple hereditary breast and ovarian cancer (HBOC) families (Ruiz-Flores P et al. Hum Mutat. 2002 Dec;20(6):474-5; Weitzel JN et al. Cancer Epidemiol Biomarkers Prev, 2005 Jul;14:1666-71; Weitzel J et al. J. Clin. Oncol. 2013 Jan;31(2):210-6; El Saghir NS et al. Oncologist, 2015 Apr;20:357-64; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3; Zayas-Villanueva OA et al. BMC Cancer, 2019 Jul;19:722). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 09, 2018	Data used in classification: This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (31) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified as pathogenic by 8 submitters on ClinVar, including accredited USA laboratories GeneDx (2017) and Ambry Genetics (2016) (PP5_sup). This variant is at the same codon as a variant classified by CanVIG-UK as Pathogenic (c.8377G>A p.Gly2793Glu). (PP5_mod). Data not used in classification: The frequency of this variant is 2/123,101 individuals (the GNOMAD population). There are additional reports of this variant in BIC(4), and BRCA2 LOVD(1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2793 of the BRCA2 protein (p.Gly2793Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80359082, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 12442275, 15889636, 16030099, 23233716, 25777348). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52569). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138). Studies have shown that this missense change results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2020	Variant summary: BRCA2 c.8377G>A (p.Gly2793Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251552 control chromosomes. c.8377G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018, Calderon-Garciduenas_2005, Ruiz-Flores_2002, Weitzel_2013, ElSaghir_2015). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired HDR (homology directed repair) activity (example, Guidugli_2013). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=7)/likely pathogenic(n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

BRCA2-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 09, 2024

The c.8377G>A variant in the BRCA2 gene is located on the exon 19 and replaces glycine with arginine at codon 2793 (p.Gly2793Arg). This variant is located in the critical DNA binding domain of the BRCA2 protein (amino acids 2481-3186). This variant has been identified in multiple individuals with breast and/or ovarian cancer (PMID: 31853058, 25777348, 30630528, 12442275). Experimental homology directed repair (HDR) activity assays have proved the negative functional impact of this variant (PMID: 23108138, 33293522, 33609447). An alternative variant disrupting the same amino acid (p.Gly2793Glu) has been interpreted as likely pathogenic (ClinVar ID: 38157). This variant has been reported in ClinVar and classified as pathogenic/likely pathogenic by multiple submitters (ID: 52569). The variant is rare in general population according to gnomAD v4.1 (2/1613808 chromosomes). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.92). Therefore, the c.8377G>A (p.Gly2793Arg) variant in the BRCA2 gene has been classified as pathogenic. -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

The BRCA2 c.8377G>A variant is predicted to result in the amino acid substitution p.Gly2793Arg. This variant has been reported in multiple unrelated individuals with a personal or family history of breast and/or ovarian cancer (Ruiz-Flores et al. 2002. PubMed ID: 12442275; Calderón-Garcidueñas et al. 2005. PubMed ID: 15889636; Weitzel et al. 2013. PubMed ID: 23233716; El Saghir et al. 2015. PubMed ID: 25777348; Rebbeck et al. 2018. PubMed ID: 29446198; Fernández-Lopez et al. 2019. PubMed ID: 30630528; Zayas-Villanueva et al. 2019. PubMed ID: 31331294). Functional assays indicate this variant impacts homology directed repair (Guidugli et al. 2013. PubMed ID: 23108138; Guidugli. 2018. PubMed ID: 29394989; Richardson et al. 2021. PubMed ID: 33609447; Hu et al. 2022. PubMed ID: 35736817). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is classified as pathogenic and likely pathogenic by multiple clinical submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52569/). Taken together, this variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.93
MutPred		0.88		Gain of MoRF binding (P = 0.0196);Gain of MoRF binding (P = 0.0196);
MVP		0.99
MPC		0.17
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs80359082; hg19: chr13-32944584;