NM_000059.4:c.9227G>A

Variant names:

• chr13-32380116-G-A
• rs80359187
• NM_000059.4:c.9227G>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.9227G>A​(p.Gly3076Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 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: "SCV002761887: Well-established functional studies show a deleterious effect of this variant (PS3).; SCV000274761: "This alteration has been predicted to be pathogenic using homology-directed DNA break repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80)."; SCV000296594: Experimental studies showed that this variant results in decreased activity in homology-directed recombination (HDR) assays (PMIDs: 23108138 (2013), 29394989 (2018), 29884841 (2019), 33609447 (2021), and 35736817 (2022)).; SCV001473600: Functional analyses indicate decreased activity in assays of homology-directed recombination (HDR) (Guidugli 2013, Guidugli 2018).; SCV001478277: The variant has a probability of pathogenicity of 1.0 (PS3_strong).; SCV001574109: Experimental studies have shown that this missense change affects BRCA2 function (PMID:19043619, 23108138, 29394989).; SCV006324383: Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:33609447, 32444794)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3076V) 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: Likely pathogenic reviewed by expert panel P:10 U:2
• Conservation: PhyloP100: 9.00
• Publications: 29 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: SCV002761887: Well-established functional studies show a deleterious effect of this variant (PS3).; SCV000274761: "This alteration has been predicted to be pathogenic using homology-directed DNA break repair (HDR) functional assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80)."; SCV000296594: Experimental studies showed that this variant results in decreased activity in homology-directed recombination (HDR) assays (PMIDs: 23108138 (2013), 29394989 (2018), 29884841 (2019), 33609447 (2021), and 35736817 (2022)).; SCV001473600: Functional analyses indicate decreased activity in assays of homology-directed recombination (HDR) (Guidugli 2013, Guidugli 2018).; SCV001478277: The variant has a probability of pathogenicity of 1.0 (PS3_strong).; SCV001574109: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 23108138, 29394989).; SCV006324383: Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:33609447, 32444794)
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 27 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 chr13-32380116-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 126203.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 13-32380116-G-A is Pathogenic according to our data. Variant chr13-32380116-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 52780.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.9227G>A	p.Gly3076Glu	missense	Exon 24 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9227G>A	p.Gly3076Glu	missense	Exon 24 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9176G>A	p.Gly3059Glu	missense	Exon 24 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.9227G>A	p.Gly3076Glu	missense	Exon 24 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9227G>A	p.Gly3076Glu	missense	Exon 24 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8858G>A	p.Gly2953Glu	missense	Exon 24 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250980 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	2	-	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
3	-	-	not provided (3)
1	-	-	BRCA2-related cancer predisposition (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		9.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.85
MutPred		0.86		Loss of sheet (P = 0.0126)
MVP		0.98
MPC		0.18
ClinPred		0.94	D
GERP RS		5.5
gMVP		0.87
Mutation Taster		=6/94	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: rs80359187; hg19: chr13-32954253;