chr13-32370447-G-A

Variant names:

• chr13-32370447-G-A
• rs80359082
• NM_000059.4:c.8377G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 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 (★★). ClinVar reports functional evidence for this variant: "SCV000073512: Experimental studies have shown that this missense change affects BRCA2 function (PMID:23108138).; SCV000695147: 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).; SCV001478305: The variant has a probability of pathogenicity of 1.0 (PS3_strong). Guidugli et al Cancer Res 2013;73:265-275,Couch Lab); SCV000108641: 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);; SCV000600799: "In addition, functional studies have shown that this variant greatly reduces the homology-directed DNA repair (HDR) activity of the BRCA2 protein." PMID:23108138; SCV000693548: Experimental studies have shown that this missense change results in homology-directed repair activity comparable to known pathogenic mutations.; SCV000683961: 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).; SCV005361511: 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).; SCV004845648: Experimental homology directed repair (HDR) activity assays have proved the negative functional impact of this variant (PMID:23108138, 33293522, 33609447).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2793V) has been classified as Likely 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:19 U:2
• Conservation: PhyloP100: 9.94
• Publications: 26 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000073512: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138).; SCV000695147: 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).; SCV001478305: The variant has a probability of pathogenicity of 1.0 (PS3_strong). Guidugli et al Cancer Res 2013;73:265-275,Couch Lab); SCV000108641: 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);; SCV000600799: "In addition, functional studies have shown that this variant greatly reduces the homology-directed DNA repair (HDR) activity of the BRCA2 protein." PMID:23108138; SCV000693548: Experimental studies have shown that this missense change results in homology-directed repair activity comparable to known pathogenic mutations.; SCV000683961: 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).; SCV005361511: 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).; SCV004845648: Experimental homology directed repair (HDR) activity assays have proved the negative functional impact of this variant (PMID: 23108138, 33293522, 33609447).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 30 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-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38158.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 52569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.8377G>A	p.Gly2793Arg	missense	Exon 19 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8377G>A	p.Gly2793Arg	missense	Exon 19 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8377G>A	p.Gly2793Arg	missense	Exon 19 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.8377G>A	p.Gly2793Arg	missense	Exon 19 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8377G>A	p.Gly2793Arg	missense	Exon 19 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8008G>A	p.Gly2670Arg	missense	Exon 19 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251416 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (7)
4	-	-	not provided (4)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	BRCA2-related disorder (1)
1	-	-	Familial cancer of breast (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.88		Gain of MoRF binding (P = 0.0196)
MVP		0.99
MPC		0.17
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.92
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80359082; hg19: chr13-32944584;