13-32397030-G-C

Variant names:

• chr13-32397030-G-C
• rs55775473
• NM_000059.4:c.9634G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.9634G>C​(p.Gly3212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3212E) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:15 O:1
• Conservation: PhyloP100: 2.13
• Publications: 18 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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007734239).
• BP6: Variant 13-32397030-G-C is Benign according to our data. Variant chr13-32397030-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38257.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.9634G>C	p.Gly3212Arg	missense	Exon 26 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9634G>C	p.Gly3212Arg	missense	Exon 26 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9583G>C	p.Gly3195Arg	missense	Exon 26 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.9634G>C	p.Gly3212Arg	missense	Exon 26 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9634G>C	p.Gly3212Arg	missense	Exon 26 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.9265G>C	p.Gly3089Arg	missense	Exon 26 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251338 AF XY: 0.000265

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.000145

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: 0.000163

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 727186

African (AFR) AF: 0.00436 AC: 146 AN: 33466

American (AMR) AF: 0.000224 AC: 10 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.000232 AC: 14 AN: 60390

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74462

African (AFR) AF: 0.00474 AC: 197 AN: 41546

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.00133

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	3	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	2	not specified (3)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.94	T
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.071	T
Sift4G	Uncertain	0.0080	D
Vest4		0.34
MutPred		0.33		Gain of solvent accessibility (P = 0.0097)
MVP		0.84
MPC		0.064
ClinPred		0.016	T
GERP RS		3.0
gMVP		0.19
Mutation Taster		=78/22	polymorphism

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: rs55775473; hg19: chr13-32971167;