rs80358979

Variant names:

• chr13-32356521-T-C
• rs80358979
• NM_000059.4:c.7529T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32356521-T-C
• chr13-32356521-T-G
• chr13-32356521-T-A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7529T>C​(p.Leu2510Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004829743: Functional studies have reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID:23108138, 29394989, 29884841, 33609447) and severely disrupts BRCA2 function in the rescue of viability, chromosomal aberrations and sensitivities to DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID:21719596)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2510T) has been classified as Uncertain significance. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 7.05
• Publications: 26 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004829743: Functional studies have reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 23108138, 29394989, 29884841, 33609447) and severely disrupts BRCA2 function in the rescue of viability, chromosomal aberrations and sensitivities to DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 21719596).; SCV000567107: Published functional studies demonstrate a damaging effect: deficient homology-directed DNA repair activity, hypersensitivity to DNA-damaging agents, deficiency in RAD51 foci formation; however reduced viability of rescued embryonic stem cells suggests this may be a hypomorphic variant (Biswas 2011, Guidugli 2018, Hart 2019, Richardson 2021); SCV000607817: Using a mouse embryonic stem cell-based functional assay and homologous recombination-mediated DNA repair (HDR) assays, this alteration has been shown to have hypersensitivity to different DNA-damaging agents, deficiency in RAD51 foci formation and homologous recombination efficiency, increased chromosomal aberrations, and reduced binding to an essential cofactor, DSS1 (Biswas K et al. Blood. 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80).; SCV004362215: Functional studies have reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 23108138, 29394989, 29884841, 33609447) and severely disrupts BRCA2 function in the rescue of viability, chromosomal aberrations and sensitivities to DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 21719596).; SCV001478276: The variant has been reported in trans with another BRCA2 variant to cause Fanconi Anaemia (Hirsch et al Blood 2004; 103:2554-2559). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong).; SCV001574248: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 21719596, 23108138, 29394989).; SCV005203096: The most pronounced variant effect results in losss of BRCA2 protein in patients cells carrying the current variant and a nonsense variant, and deleterious HDR by a gold-standard HDR assay (Hirsch_2004, Hu_2022).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 33 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 13-32356521-T-C is Pathogenic according to our data. Variant chr13-32356521-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9345.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.7529T>C	p.Leu2510Pro	missense	Exon 15 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7529T>C	p.Leu2510Pro	missense	Exon 15 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7529T>C	p.Leu2510Pro	missense	Exon 15 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.7529T>C	p.Leu2510Pro	missense	Exon 15 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7529T>C	p.Leu2510Pro	missense	Exon 15 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7160T>C	p.Leu2387Pro	missense	Exon 15 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000333 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MutPred		0.94		Loss of sheet (P = 0.0084)
MVP		0.99
MPC		0.19
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.79
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs80358979; hg19: chr13-32930658;