rs786201916

Variant names:

• chr13-32319325-G-A
• rs786201916
• NM_000059.4:c.316G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32319325-G-A
• chr13-32319325-G-C
• chr13-32319325-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM2 PP3

The NM_000059.4(BRCA2):​c.316G>A​(p.Gly106Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★). ClinVar reports functional evidence for this variant: "SCV000215084: Molecular studies showed mouse embryonic stem cells with this variant had poor complementation and were sensitive to DNA damaging agents (Tubeuf H et al. Cancer Res, 2020 Sep" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G106E) has been classified as Uncertain significance. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 1.35
• Publications: 9 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000215084: Molecular studies showed mouse embryonic stem cells with this variant had poor complementation and were sensitive to DNA damaging agents (Tubeuf H et al. Cancer Res, 2020 Sep;80:3593-3605).; SCV000759018: Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32641407).; SCV001362012: The variant allele was found at a frequency of 4e-06 in 249688 control chromosomes. c.316G>A has been reported in the literature as a maternally inherited allele in a compound heterozygous genotype in at-least one individual affected with Fanconi Anemia (example, Radulovic_2023 cited in Tubeuf_2020). Tubeuf_2020 Internal structural analysis indicates that this variant disrupts the characteristic motif of collagen and inserts a bulky sidechain into a sterically constrained region (Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Bella J et al. Science. 1994;266:75-81). However, the most relevant part is: > "experimental evidence that this variant affects mRNA splicing demonstrating a partial level of out of frame exon 3 skipping in >60% of transcripts (Tubeuf_2020)" So the correct output should be: > "experimental evidence that this variant affects mRNA splicing demonstrating a partial level of out of frame exon 3 skipping in >60% of transcripts (Tubeuf_2020)"
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.316G>A	p.Gly106Arg	missense splice_region	Exon 3 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.316G>A	p.Gly106Arg	missense splice_region	Exon 3 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.316G>A	p.Gly106Arg	missense splice_region	Exon 3 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.316G>A	p.Gly106Arg	missense splice_region	Exon 3 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.316G>A	p.Gly106Arg	missense splice_region	Exon 3 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.-54G>A		splice_region	Exon 3 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249688 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458908 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725898

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109474

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	BRCA2-related cancer predisposition (1)
1	-	-	Fanconi anemia (1)
1	-	-	Fanconi anemia complementation group D1 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.93	T
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.093	T
Sift4G	Benign	0.14	T
Vest4		0.41
MutPred		0.28		Gain of MoRF binding (P = 0.0166)
MVP		0.91
MPC		0.077
ClinPred		0.46	T
GERP RS		3.3
gMVP		0.25
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: 0

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

Other links and lift over

dbSNP: rs786201916; hg19: chr13-32893462;