chr1-45331556-C-T

Variant names:

• chr1-45331556-C-T
• rs36053993
• NM_001128425.2:c.1187G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PM1 PM5 PP3 PP5_Very_Strong BS1_Supporting BS2_Supporting

The NM_001128425.2(MUTYH):​c.1187G>A​(p.Gly396Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00473 in 1,613,938 control chromosomes in the GnomAD database, including 26 homozygotes. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G396S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (25 hom.)
• Consequence: MUTYH NM_001128425.2 missense, splice_region
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:76 O:4
• Conservation: PhyloP100: 4.51
• Publications: 471 publications found

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 30 uncertain in NM_001128425.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45331661-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421574.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-45331556-C-T is Pathogenic according to our data. Variant chr1-45331556-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00488 (7127/1461596) while in subpopulation NFE AF = 0.00591 (6576/1112006). AF 95% confidence interval is 0.00579. There are 25 homozygotes in GnomAdExome4. There are 3446 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. 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
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1187G>A	p.Gly396Asp	missense splice_region	Exon 13 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1103G>A	p.Gly368Asp	missense splice_region	Exon 13 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1178G>A	p.Gly393Asp	missense splice_region	Exon 13 of 16	NP_036354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1187G>A	p.Gly396Asp	missense splice_region	Exon 13 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1103G>A	p.Gly368Asp	missense splice_region	Exon 13 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1178G>A	p.Gly393Asp	missense splice_region	Exon 13 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 506 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00303 AC: 756 AN: 249742 AF XY: 0.00300

Gnomad AFR exome AF: 0.000821

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00488 AC: 7127 AN: 1461596 Hom.: 25 Cov.: 33 AF XY: 0.00474 AC XY: 3446 AN XY: 727082

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00320 AC: 143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00177 AC: 94 AN: 53136

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00591 AC: 6576 AN: 1112006

Other (OTH) AF: 0.00449 AC: 271 AN: 60390

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00315 AC XY: 235 AN XY: 74494

African (AFR) AF: 0.00108 AC: 45 AN: 41572

American (AMR) AF: 0.00412 AC: 63 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00459 Hom.: 6

Bravo AF: 0.00371

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
32	-	-	Familial adenomatous polyposis 2 (35)
19	-	-	not provided (19)
10	-	-	Hereditary cancer-predisposing syndrome (10)
2	-	-	Carcinoma of colon (2)
1	-	-	Breast carcinoma (1)
1	-	-	Colon cancer (1)
1	-	-	Colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas (1)
1	-	-	Diffuse midline glioma, H3 K27-altered (1)
1	-	-	Endometrial cancer (1)
1	-	-	Familial colorectal cancer (1)
1	-	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)
1	-	-	Inherited polyposis and early onset colorectal cancer - germline testing (1)
1	-	-	MUTYH-related disorder (1)
1	-	-	Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 (1)
1	-	-	Neoplasm of stomach;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		1.0
MPC		0.63
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.70
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.020		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: rs36053993; hg19: chr1-45797228; COSMIC: COSV58343811; COSMIC: COSV58343811;