13-32340455-C-T

Variant names:

• chr13-32340455-C-T
• rs1799954
• NM_000059.4:c.6100C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000059.4(BRCA2):​c.6100C>T​(p.Arg2034Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,613,692 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2034L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:46 O:1
• Conservation: PhyloP100: -0.243
• Publications: 73 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006237477).
• BP6: Variant 13-32340455-C-T is Benign according to our data. Variant chr13-32340455-C-T is described in ClinVar as Benign. ClinVar VariationId is 41558.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.6100C>T	p.Arg2034Cys	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.6100C>T	p.Arg2034Cys	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.6100C>T	p.Arg2034Cys	missense	Exon 11 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.6100C>T	p.Arg2034Cys	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.6100C>T	p.Arg2034Cys	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.5731C>T	p.Arg1911Cys	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 515 AN: 152148 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00313 AC: 785 AN: 250958 AF XY: 0.00312

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00463 AC: 6768 AN: 1461426 Hom.: 19 Cov.: 46 AF XY: 0.00446 AC XY: 3240 AN XY: 727016

African (AFR) AF: 0.00167 AC: 56 AN: 33468

American (AMR) AF: 0.00409 AC: 183 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39648

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53310

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.00558 AC: 6201 AN: 1111760

Other (OTH) AF: 0.00434 AC: 262 AN: 60378

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152266 Hom.: 3 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74460

African (AFR) AF: 0.00144 AC: 60 AN: 41570

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00534 AC: 363 AN: 67982

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00458 Hom.: 13

Bravo AF: 0.00383

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00605

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	13	Breast-ovarian cancer, familial, susceptibility to, 2 (15)
-	-	12	not specified (13)
-	-	7	not provided (7)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	2	Familial cancer of breast (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.24
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.016	D
Sift4G	Benign	0.16	T
Vest4		0.20
MVP		0.83
MPC		0.022
ClinPred		0.022	T
GERP RS		1.8
gMVP		0.22
Mutation Taster		=99/1	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: rs1799954; hg19: chr13-32914592; COSMIC: COSV66461677;