13-32346896-G-C

Variant names:

• chr13-32346896-G-C
• rs28897743
• NM_000059.4:c.7007G>C

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.7007G>C​(p.Arg2336Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,450,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000073126: Studies have shown that this missense change results in skipping of exons 12 and 13, and produces a non-functional protein and/or introduces a premature termination codon (PMID:22505045)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 4.66
• Publications: 117 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: SCV000073126: Studies have shown that this missense change results in skipping of exons 12 and 13, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22505045).; SCV000821714: Experimental studies have shown that this missense change causes skipping of exons 12 and 13 (PMID: 22505045).; SCV006324388: Reported by one calibrated study incorporating mRNA splicing effect to exhibit function similar to pathogenic control variants (PMID:33293522); SCV000276750: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Houdayer C et al. Hum. Mutat. 2012 Aug; 33(8):1228-38; Ambry internal data).; SCV000683838: A functional study reported that this variant impacted BRCA2 function in the rescue of Brca2-deficient mouse ES cells and the lack of detectable protein expression (PMID: 33293522).; SCV000592087: 'RNA was extracted from lymphoblastoid cell lines and an increase of alternative splicing was observed ('Exons 12 and 13 skipped'), increasing the likelihood this variant has clinical significance (Houdayer 2012).'
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 13-32346896-G-C is Pathogenic according to our data. Variant chr13-32346896-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52241.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.7007G>C	p.Arg2336Pro	missense splice_region	Exon 13 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7007G>C	p.Arg2336Pro	missense splice_region	Exon 13 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7007G>C	p.Arg2336Pro	missense splice_region	Exon 13 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.7007G>C	p.Arg2336Pro	missense splice_region	Exon 13 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7007G>C	p.Arg2336Pro	missense splice_region	Exon 13 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.6638G>C	p.Arg2213Pro	missense splice_region	Exon 13 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247222 AF XY: 0.00000748

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450870 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.00 AC: 0 AN: 84726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105500

Other (OTH) AF: 0.0000167 AC: 1 AN: 59960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000270 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary breast ovarian cancer syndrome (5)
4	-	-	not provided (4)
3	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Fanconi anemia complementation group D1 (1)
1	-	-	Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Benign	0.95
Eigen	Benign	-0.058
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.71	T
PhyloP100		4.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.42
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Vest4		0.38
MutPred		0.43		Gain of glycosylation at R2336 (P = 0.0157)
MVP		0.91
MPC		0.061
ClinPred		0.83	D
GERP RS		5.0
gMVP		0.31
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.18		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: rs28897743; hg19: chr13-32921033;