NM_000059.4:c.8486A>G

Variant names:

• chr13-32370556-A-G
• rs80359100
• NM_000059.4:c.8486A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PM5 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8486A>G​(p.Gln2829Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,456,384 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002761851: Independent splicing assays confirm this variant disrupts normal mRNA splicing, causing in-frame skipping of exon 19 resulting in a transcript that encodes loss of 51 amino acids from the highly conserved DNA binding domain important to normal BRCA2 function (Houdayer et al., 2012 PMID:22505045, Acedo et al., 2015 PMID:25382762, Kraus et., 2017 PMID:27616075, Wai et al., 2020 PMID:32123317) (PVS1_O_Strong).; SCV004362752: "A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID:33293522)."; SCV000695156: One functional study, Houdayer _2012, testing this variant in lymphocytes found it to cause an inframe mutation resulting in exon 19 skipping, with no wildtype transcript being produced.; SCV001470248: Experimental studies show the variant is damaging to protein function by reducing cell survival (PMID:33293522 (2020)) and causing improper splicing of exon 19 (PMIDs: 34663891 (2021), 32123317 (2020), 27060066 (2016), 22505045 (2012), 16489001 (2006)).; SCV005425800: "A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID:33293522)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2829K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 5.99
• Publications: 21 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002761851: Independent splicing assays confirm this variant disrupts normal mRNA splicing, causing in-frame skipping of exon 19 resulting in a transcript that encodes loss of 51 amino acids from the highly conserved DNA binding domain important to normal BRCA2 function (Houdayer et al., 2012 PMID:22505045, Acedo et al., 2015 PMID:25382762, Kraus et., 2017 PMID:27616075, Wai et al., 2020 PMID:32123317) (PVS1_O_Strong).; SCV004362752: "A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522)."; SCV000695156: One functional study, Houdayer _2012, testing this variant in lymphocytes found it to cause an inframe mutation resulting in exon 19 skipping, with no wildtype transcript being produced.; SCV001470248: Experimental studies show the variant is damaging to protein function by reducing cell survival (PMID: 33293522 (2020)) and causing improper splicing of exon 19 (PMIDs: 34663891 (2021), 32123317 (2020), 27060066 (2016), 22505045 (2012), 16489001 (2006)).; SCV005425800: "A functional study has reported this variant impacts BRCA2 function in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522)."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32370556-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1484629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 13-32370556-A-G is Pathogenic according to our data. Variant chr13-32370556-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38161.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.8486A>G	p.Gln2829Arg	missense splice_region	Exon 19 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8486A>G	p.Gln2829Arg	missense splice_region	Exon 19 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8486A>G	p.Gln2829Arg	missense splice_region	Exon 19 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.8486A>G	p.Gln2829Arg	missense splice_region	Exon 19 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8486A>G	p.Gln2829Arg	missense splice_region	Exon 19 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8117A>G	p.Gln2706Arg	missense splice_region	Exon 19 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456384 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724932

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107092

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
2	-	-	BRCA2-related cancer predisposition (2)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.040	T
PhyloP100		6.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Vest4		0.62
MutPred		0.36		Gain of MoRF binding (P = 0.018)
MVP		0.93
MPC		0.17
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.76
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359100; hg19: chr13-32944693;