rs80359083

Positions:

• chr13-32370448-G-A
• chr13-32370448-G-C
• chr13-32370448-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8378G>A​(p.Gly2793Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 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: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32370448-G-AA is described in ClinVar as [Pathogenic]. Clinvar id is 254622.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 13-32370448-G-A is Pathogenic according to our data. Variant chr13-32370448-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8378G>A	p.Gly2793Glu	missense_variant	19/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8378G>A	p.Gly2793Glu	missense_variant	19/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 14, 2019	Data used in classification: Case control comparison of UK familial cases against ethnically matched population data (5/25,773 in familial UK cases against 0/56,856 GNOMAD NFE controls) 2-sided Fishers exact: pexact= 0.0030 (PS4_strong). Absent in the remainder of the gnomAD population (PM2_mod). This variant is predicted deleterious on AlignGVGD (class:C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging), CADD (29.8), Revel [0-1]: 0.916, Gavin class: Pathogenic, (confidence: genomewide) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay DNA Binding Domain assay (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of P=1.0 (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (5), DMuDB (1), BIC(4), and BRCA2 LOVD(1). 5 Classifications on ClinVar as uncertain. Ambry classification: likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: BRCA2 c.8378G>A (p.Gly2793Glu) 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 was absent in 251422 control chromosomes (gnomAD). c.8378G>A has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (example: Butz_2021). The variant of interest has been functionally assessed for effect on splicing and showed that it did influence exon 19 splicing (~15%), with the predominant product being the wild type BRCA2 protein (~85%) (Acedo_2012), additionally, the variant of interest was shown to significantly affect homology-directed repair activity (example: Guidugli_2013, Richardson_2021). Other variants affecting the same amino acid residue is classified pathogenic/likely pathogenic in ClinVar (CV ID 52569, 38158). This suggests that this residue may play a critical role in normal protein function. The following publications have been ascertained in the context of this evaluation (PMID: 22632462, 33672545, 32719484, 23108138, 24323938, 19043619, 33609447). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 09, 2024	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): LOF in HRD-Assay (Richardson et al., (PMID:33609447) Own RNA-Analysis in patient derived blood sample revealed biallelic expression of variant in WT-transcript, PM2 (supporting pathogenic): not in gnomAD, PP3 (supporting pathogenic): CADD:29.5 REVEL: 0.916 HCI prior:0.81 BayesDEL:0.583972 spliceAI:BRCA2: 0.05 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2793 of the BRCA2 protein (p.Gly2793Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 38157). 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, 29394989, 29884841). This variant disrupts the p.Gly2793 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12442275, 15889636, 16030099, 19043619, 23108138, 23233716, 25085752, 25777348). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This missense variant replaces glycine with glutamic acid 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 shown that this variant results in impaired homology-directed DNA repair (PMID: 23108138, 29394989, 33609447) and abnormal splicing (PMID: 22632462). This variant has been reported in 3 individuals affected with breast or ovarian cancer (PMID: 33672545, Lovejoy 2018, Color internal data). Another variant at this amino acid (Gly2793Arg) has been classified as pathogenic (ClinVar Variant ID: 52569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, flagged submission	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jul 07, 2000	- -
Uncertain significance, flagged submission	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 08, 2010	- -

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2023	Published functional studies demonstrate a damaging effect: significantly reduced homologous recombination DNA-repair activity (Guidugli et al., 2013; Guidugli et al., 2018; Iversen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer (Lovejoy et al., 2018; Butz et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8606G>A; This variant is associated with the following publications: (PMID: 23108138, 24323938, 32623769, 25382762, 33609447, 33672545, 32170000, 19043619, 22632462, 12228710, 29884841, 32719484, 35665744, 10923033, 29394989) -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 12, 2024	A hybrid minigene functional assay has demonstrated skipping of exon 19 in the BRCA2 gene from this variant (Acedo et al. 2012. PubMed ID: 22632462). Another functional study shows that this variant causes reduced protein function compared to wildtype (Guidugli et al. 2012. PubMed ID: 23108138). Alternate missense changes at this amino acid (p.Gly2793Arg, p.Gly2793Val) are classified as pathogenic (Richardson et al. 2021. PubMed ID: 33609447). Although the classifications in ClinVar range from uncertain to pathogenic, the vast majority of recent entries are likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38157/). This variant has not been observed in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Uncertain significance, flagged submission	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2023	In the published literature, this variant has been reported in an individual with male breast cancer who had a late age of onset (PMID: 33609447 (2021)) as well as individuals who underwent genetic testing for BRCA1 and BRCA2 (PMID: 23108138 (2013)). Functional studies indicate that this variant reduces the homology-directed DNA repair (HDR) activity of the BRCA2 protein (PMID: 23108138 (2013), 29394989 (2018), 29884841 (2019)), and is predicted to be likely deleterious based on protein likelihood ratio modeling (PMID: 19043619 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This missense variant replaces glycine with glutamic acid 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 shown that this variant results in impaired homology-directed DNA repair (PMID: 23108138, 29394989, 33609447) and abnormal splicing (PMID: 22632462). This variant has been reported in 3 individuals affected with breast or ovarian cancer (PMID: 33672545, Lovejoy 2018, Color internal data). Another variant at this amino acid (Gly2793Arg) has been classified as pathogenic (ClinVar Variant ID: 52569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2023	The p.G2793E variant (also known as c.8378G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8378. The glycine at codon 2793 is replaced by glutamic acid, an amino acid with similar properties. This alteration was found to produce exon 19 skipping; however, the majority of transcript produced by this alteration is wildtype (Acedo A et al. Breast Cancer Res. 2012 May;14:R87). This amino acid substitution was shown to be defective in a homology directed repair assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). Based on internal structural analysis, this alteration is predicted to disrupt binding to DSS1 and is more destabilizing to the local structure than other known pathogenic variants (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
MutPred		0.82		Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);
MVP		0.99
MPC		0.18
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80359083; hg19: chr13-32944585; COSMIC: COSV104701295; COSMIC: COSV104701295;