rs15869

Variant names:

• chr13-32398875-A-C
• rs15869
• NM_000059.4:c.*105A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32398875-A-C
• chr13-32398875-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.*105A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,401,318 control chromosomes in the GnomAD database, including 29,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2346 hom., cov: 33)
  • Exomes 𝑓: 0.20 (26966 hom.)
• Consequence: BRCA2 NM_000059.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 0.0360
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-32398875-A-C is Benign according to our data. Variant chr13-32398875-A-C is described in ClinVar as Benign. ClinVar VariationId is 125927.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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.*105A>C		3_prime_UTR	Exon 27 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.*105A>C		3_prime_UTR	Exon 27 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.*105A>C		3_prime_UTR	Exon 27 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.*105A>C		3_prime_UTR	Exon 27 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.*105A>C		3_prime_UTR	Exon 27 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.*105A>C		3_prime_UTR	Exon 27 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23820 AN: 152148 Hom.: 2348 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.204 AC: 255301 AN: 1249052 Hom.: 26966 Cov.: 17 AF XY: 0.204 AC XY: 126307 AN XY: 618432

African (AFR) AF: 0.0366 AC: 981 AN: 26782

American (AMR) AF: 0.103 AC: 2603 AN: 25200

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 2928 AN: 21094

East Asian (EAS) AF: 0.191 AC: 6804 AN: 35554

South Asian (SAS) AF: 0.211 AC: 13960 AN: 66100

European-Finnish (FIN) AF: 0.213 AC: 7830 AN: 36732

Middle Eastern (MID) AF: 0.233 AC: 878 AN: 3774

European-Non Finnish (NFE) AF: 0.213 AC: 209145 AN: 981472

Other (OTH) AF: 0.194 AC: 10172 AN: 52344

GnomAD4 genome AF: 0.156 AC: 23811 AN: 152266 Hom.: 2346 Cov.: 33 AF XY: 0.156 AC XY: 11629 AN XY: 74432

African (AFR) AF: 0.0432 AC: 1798 AN: 41576

American (AMR) AF: 0.116 AC: 1773 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1161 AN: 5182

South Asian (SAS) AF: 0.230 AC: 1112 AN: 4830

European-Finnish (FIN) AF: 0.213 AC: 2254 AN: 10586

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14568 AN: 68002

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.192 Hom.: 5895

Bravo AF: 0.144

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Breast-ovarian cancer, familial, susceptibility to, 2 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.2
DANN	Benign	0.43
PhyloP100		0.036
Mutation Taster		=100/0	polymorphism (auto)

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: rs15869; hg19: chr13-32973012; COSMIC: COSV100583075; COSMIC: COSV100583075;