rs80359071

chr13-32363445-G-Achr13-32363445-G-Cchr13-32363445-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.8243G>A(p.Gly2748Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2748S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:23 U:1
• Conservation: PhyloP100: 7.77

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 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 chr13-32363444-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409429.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 13-32363445-G-A is Pathogenic according to our data. Variant chr13-32363445-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52535.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363445-G-A is described in Lovd as [Pathogenic]. Variant chr13-32363445-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8243G>A	p.Gly2748Asp	missense_variant	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8243G>A	p.Gly2748Asp	missense_variant	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249060 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134772

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000395 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 23, 2021	The BRCA2 c.8243G>A; p.Gly2748Asp variant (rs80359071) is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Bhaskaran 2019, Claes 2004, Easton 2007). This variant is also reported in ClinVar (Variation ID: 52535), and classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 2748 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.877). Functional analyses of the variant protein show impaired homology directed repair activity (Balia 2011, Farrugia 2008, Guidugli 2013). Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Balia C et al. Effect of the overexpression of BRCA2 unclassified missense variants on spontaneous homologous recombination in human cells. Breast Cancer Res Treat. 2011 Oct;129(3):1001-9. PMID: 21671020. Bhaskaran SP et al. Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients. Int J Cancer. 2019 Aug 15;145(4):962-973. PMID: 30702160. Claes K et al. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. PMID: 15026808. Easton DF et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 Nov;81(5):873-83. PMID: 17924331. Farrugia DJ et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. PMID: 18451181. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. PMID: 23108138. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	Published functional studies demonstrate a damaging effect: decreased homology-directed repair activity, increased centrosome amplification, and inability to rescue BRCA2-deficiency (PMID: 18451181, 23108138, 23328489, 25146914, 29884841, 35736817); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 35665744, 17924331, 21990134); Observed in multiple individuals with personal and family history consistent with pathogenic variants in this gene (PMID: 15026808, 17924331, 18451181, 25447315, 26824983); 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 8471G>A; This variant is associated with the following publications: (PMID: 26824983, 24504028, 25504618, 30078507, 29446198, 25447315, 19043619, 21671020, 18451181, 23108138, 25146914, 23328489, 24323938, 17924331, 25085752, 15026808, 18403564, 26269718, 29394989, 29922827, 28726806, 29988080, 30720243, 30702160, 32444794, 31447099, 32029870, 29884841, 33964450, 30787465, 33978741, 36061650, 36249907, 34906479, 28888541, 31825140, 33609447, 35665744, 35736817, 35264596, 21990134, 12228710) -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Gly2748Asp variant has been reported in the literature in 3/3590 proband chromosomes of individuals with hereditary breast and ovarian cancer and ovarian carcinoma, although no control chromosomes were tested to establish the frequency in the general population (Alsop 2012, Balia 2011, Claes 2004, Farrugia 2008, Karchin 2008, Lindor 2012, Easton 2007). The p.Gly2748 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) suggest that the p.Gly2748Asp variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant is listed in the dbSNP database (ID#:rs80359071) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. In a study that interrogated the Myriad Genetic Laboratories database to assess the clinical significance of BRCA1/2 sequence variants, segregation studies and statistical analyses suggested the p.G2748D variant was in “favour of causality” (Easton 2007). In addition, functional studies have shown that the homologous recombination repair activity is compromised, as determined by transient overexpression of this variant protein, and that it leads to an increase in the proportion of cells undergoing aberrant centriole amplification (Balia 2011, Farrugia 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 11, 2020	This variant has been reported in individuals affected with breast cancer in the published literature (PMID: 24323938 (2014), 23108138 (2013), 17924331 (2007), 15026808 (2004)). Additionally, functional studies have demonstrated a damaging effect of this variant on BRCA2 protein function (PMID: 25146914 (2014), 23328489 (2013), 18451181 (2007)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 29, 2022	PP3, PP5, PM1, PM2, PS3 -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 05, 2018	This c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patients [PMID 15026808, 22711857] while only observed with extremely low allele frequency in general population according to gnomad database. Glycine at amino acid position 2748 is highly conserved during evolution. Functional studies showed that this mutant causes reduced homology-directed recombination repair activity, compared to wild type [PMID:18451181, 23328489, 25146914]. Multiple in silico predictions suggest this glycine to asparatic acid change is deleterious. Based upon above evidences, this c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene is classified as pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces glycine with aspartic acid at codon 2748 in the DNA binding domain 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 found the variant protein to be defective in homology-directed DNA repair assays in mammalian and yeast cells and in corroborating assays (PMID: 18451181, 23108138, 23328489, 25146914, 29394989, 29988080, 33609447, 33978741, 35736817). This variant has been reported in at least 10 individuals and families with history of breast and/or ovarian cancer (PMID: 15026808, 18451181, 22711857, 26824983, 30078507, 30702160). This variant has been identified in 2/249060 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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 28, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 26, 2010	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2021	Variant summary: BRCA2 c.8243G>A (p.Gly2748Asp) results in a non-conservative amino acid change located in the BRCA2, OB1 domain 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 7.9e-06 in 252586 control chromosomes. c.8243G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic cancer (example, Li_2018, Hu_2018, Lin_2016, Alsop_2012 and Claes_2004, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Multiple independent functional studies demonstrated a deleterious impact by the variant resulting in impaired homologous recombination activity of BRCA2 and inability to complement the loss of cell viability in mouse embryonic stem cell-based functional assays, further supporting a disease-causing impact (Guidugli_2018, Mesman_2018, Hendriks_2014, Guidugli_2012, and Farrugia_2009). Multiple clinical diagnostic laboratories, a consortium (CIMBA) and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2016	The p.Gly2748Asp variant in BRCA2 has been reported in at least 10 individuals w ith BRCA2-associated cancers (Claes 2014, Breast Cancer Information Core (BIC) d atabase), and it was absent from large population studies. In vitro functional s tudies provide some evidence that the p.Gly2748Asp variant may impact protein fu nction (Guidugli 2014, Spugnesi 2013). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Cl inVar SCV000244484.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2748 of the BRCA2 protein (p.Gly2748Asp). This variant is present in population databases (rs80359071, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15026808, 17924331, 22711857). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52535). 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: 18451181, 21671020, 23108138, 23328489, 25146914). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2023	This missense variant replaces glycine with aspartic acid at codon 2748 in the DNA binding domain 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 found the variant protein to be defective in homology-directed DNA repair assays in mammalian and yeast cells and in corroborating assays (PMID: 18451181, 23108138, 23328489, 25146914, 29394989, 29988080, 33609447, 33978741, 35736817). This variant has been reported in at least 10 individuals and families with history of breast and/or ovarian cancer (PMID: 15026808, 18451181, 22711857, 26824983, 30078507, 30702160). This variant has been identified in 2/249060 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	Ambry Genetics	Nov 05, 2021	The p.G2748D pathogenic variant (also known as c.8243G>A), located in coding exon 17 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8243. The glycine at codon 2748 is replaced by aspartic acid, an amino acid with very few similar properties. This alteration, also referred to as 8471G>A in some literature, behaves as non-functional in multiple assays including a homologous repair assay, a Brca2-null mouse embryonic stem cell complementation assay, and a PARP inhibitor assay (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Hum. Mutat. 2014 Feb;35:151-64; Guidugli L et al. Am J Hum Genet. 2018 Feb 1;102(2):233-248; Mesman RLS et al. Genet Med. 2018 Jul 10; Ikegami M. et al. Nat Commun. 2020 May;11(1):2573). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The variant has been reported in multiple individuals with HBOC in the literature and is considered pathogenic by a multifactorial analysis model of variant interpretation which demonstrated strong co-segregation and family history scores (Rebbeck TR. Hum Mutat. 2018 May;39(5):593-620; Easton DF et al. Am J Hum Genet, 2007 Nov;81:873-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.76
MutPred		0.94		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.98
MPC		0.18
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs80359071; hg19: chr13-32937582; COSMIC: COSV99061699; COSMIC: COSV99061699;