13-32363445-G-A

Variant names:

• chr13-32363445-G-A
• rs80359071
• NM_000059.4:c.8243G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 (★★★). ClinVar reports functional evidence for this variant: "SCV000073473: Experimental studies have shown that this missense change affects BRCA2 function (PMID:18451181, 21671020, 23108138, 23328489, 25146914)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2748V) 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:24 U:1
• Conservation: PhyloP100: 7.77
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073473: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 21671020, 23108138, 23328489, 25146914).; SCV000605806: "In vitro functional studies provide some evidence that the p.Gly2748Asp variant may impact protein function" (Guidugli 2014, Spugnesi 2013).; SCV000695136: 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).; SCV005373764: Ikegami 2022, Mesman 2019,... (Table 9 ClinGen ENIGMA Guidelines); SCV000839922: Functional studies showed that this mutant causes reduced homology-directed recombination repair activity, compared to wild type [PMID:18451181, 23328489, 25146914].; SCV004845625: 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).; SCV000274383: 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).; SCV000689109: Functional studies have found this 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, 29988080, 32444794, 33609447, 35736817, 39779857).; SCV000296703: "Additionally, functional studies have demonstrated a damaging effect of this variant on BRCA2 protein function." PMID:25146914 (2014), 23328489 (2013), 18451181 (2007); SCV000568124: "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)"; SCV000592180: "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)."; SCV002048649: Functional analyses of the variant protein show impaired homology directed repair activity (Balia 2011, Farrugia 2008, Guidugli 2013). PMID: 21671020. PMID: 18451181. PMID: 23108138.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32363445-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1171382.
• 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 VariationId is 52535.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.8243G>A	p.Gly2748Asp	missense	Exon 18 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8243G>A	p.Gly2748Asp	missense	Exon 18 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8243G>A	p.Gly2748Asp	missense	Exon 18 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8243G>A	p.Gly2748Asp	missense	Exon 18 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8243G>A	p.Gly2748Asp	missense	Exon 18 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7874G>A	p.Gly2625Asp	missense	Exon 18 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249060 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000413 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
6	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (7)
5	-	-	Hereditary breast ovarian cancer syndrome (5)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial cancer of breast (1)
1	-	-	Gastric cancer (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.76
MutPred		0.94		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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

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