rs4987046

Variant names:

• chr13-32319134-A-G
• rs4987046
• ENST00000530893.7:c.-245A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32319134-A-G
• chr13-32319134-A-C
• chr13-32319134-A-T

Variant summary

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

The NM_001406722.1(BRCA2):​c.-245A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,770 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: BRCA2 NM_001406722.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:2 B:38 O:2
• Conservation: PhyloP100: 0.845
• Publications: 80 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=0.009805024).
• BP6: Variant 13-32319134-A-G is Benign according to our data. Variant chr13-32319134-A-G is described in ClinVar as Benign. ClinVar VariationId is 37734.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406722.1. 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.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001406722.1		c.-245A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 24	NP_001393651.1
	BRCA2	NM_001432077.1		c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	NP_001419006.1	A0A7P0T9D7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000530893.7	TSL:1	c.-245A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 27	ENSP00000499438.2	A0A590UJI7
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.125A>G	p.Tyr42Cys	missense	Exon 3 of 27	ENSP00000439902.1	P51587

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 251278 AF XY: 0.00169

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00213 AC: 3109 AN: 1461456 Hom.: 10 Cov.: 32 AF XY: 0.00215 AC XY: 1563 AN XY: 727048

African (AFR) AF: 0.000120 AC: 4 AN: 33464

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.00238 AC: 205 AN: 86254

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53404

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00227 AC: 2521 AN: 1111648

Other (OTH) AF: 0.00222 AC: 134 AN: 60386

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74484

African (AFR) AF: 0.000529 AC: 22 AN: 41558

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

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

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00248 AC: 169 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00169 AC: 205

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	12	Breast-ovarian cancer, familial, susceptibility to, 2 (13)
-	-	10	not specified (11)
-	1	4	not provided (5)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Familial cancer of breast (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.6
DANN	Benign	0.49
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.76	T
PhyloP100		0.84
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.089
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Vest4		0.31
MVP		0.78
MPC		0.023
ClinPred		0.0018	T
GERP RS		0.28
gMVP		0.40
Mutation Taster		=80/20	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: rs4987046; hg19: chr13-32893271; COSMIC: COSV104701240; COSMIC: COSV104701240;