NM_000059.4:c.9257-75G>C

Variant names:

• chr13-32394614-G-C
• rs276174922
• NM_000059.4:c.9257-75G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000059.4(BRCA2):​c.9257-75G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000087 in 1,517,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.0900
• Publications: 0 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):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-32394614-G-C is Benign according to our data. Variant chr13-32394614-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 52794.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9257-75G>C		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.9257-75G>C		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.9206-75G>C		intron	N/A	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9257-75G>C		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9257-75G>C		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8888-75G>C		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000864 AC: 118 AN: 1365690 Hom.: 0 AF XY: 0.0000940 AC XY: 64 AN XY: 680696

African (AFR) AF: 0.00 AC: 0 AN: 30994

American (AMR) AF: 0.0000256 AC: 1 AN: 39016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00 AC: 0 AN: 79030

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3940

European-Non Finnish (NFE) AF: 0.000106 AC: 111 AN: 1044512

Other (OTH) AF: 0.0000879 AC: 5 AN: 56876

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.64
PhyloP100		-0.090
Mutation Taster		=100/0	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: rs276174922; hg19: chr13-32968751;