NM_001128425.2:c.1038G>A

Variant names:

• chr1-45331809-C-T
• rs372673338
• NM_001128425.2:c.1038G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PP3_Moderate PP5

The NM_001128425.2(MUTYH):​c.1038G>A​(p.Ser346Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,609,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000216559: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV000545703: Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID:21520333, 30833417; internal data).; SCV005204925: The variant allele was found at a frequency of 4.5e-05 in 242534 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.1038G>A has been reported in the literature in the simple heterozygous, presumed compound heterozygous, or compound heterozygous state in multiple individuals affected with MUTYH-Associated Polyposis, pancreatic ductal adenocarcinoma, and/or breast cancer (example, Kairupan_2005, Olschwang_2007, Tung_2015, Thibodeau_2019). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID:15761860, 17949294, 30833417, 25186627). no; SCV000321910: Splice variant demonstrated to result in the creation of novel splice acceptor site which may result in the deletion of 14 amino acids of exon 12 (PMID:30833417)". Synonymous variant affecting the same amino acid position (i.e. S346S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (1 hom.)
• Consequence: MUTYH NM_001128425.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:4
• Conservation: PhyloP100: -2.66
• Publications: 11 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• 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: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000216559: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV000545703: Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 21520333, 30833417; internal data).; SCV005204925: The variant allele was found at a frequency of 4.5e-05 in 242534 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (4.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.1038G>A has been reported in the literature in the simple heterozygous, presumed compound heterozygous, or compound heterozygous state in multiple individuals affected with MUTYH-Associated Polyposis, pancreatic ductal adenocarcinoma, and/or breast cancer (example, Kairupan_2005, Olschwang_2007, Tung_2015, Thibodeau_2019). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15761860, 17949294, 30833417, 25186627). no; SCV000321910: Splice variant demonstrated to result in the creation of novel splice acceptor site which may result in the deletion of 14 amino acids of exon 12 (PMID: 30833417)
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-45331809-C-T is Pathogenic according to our data. Variant chr1-45331809-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 186251.

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.1038G>A	p.Ser346Ser	synonymous	Exon 12 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.954G>A	p.Ser318Ser	synonymous	Exon 12 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1029G>A	p.Ser343Ser	synonymous	Exon 12 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1038G>A	p.Ser346Ser	synonymous	Exon 12 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.954G>A	p.Ser318Ser	synonymous	Exon 12 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1029G>A	p.Ser343Ser	synonymous	Exon 12 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000454 AC: 11 AN: 242534 AF XY: 0.0000456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000672 AC: 98 AN: 1457854 Hom.: 1 Cov.: 33 AF XY: 0.0000662 AC XY: 48 AN XY: 724900

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

American (AMR) AF: 0.00 AC: 0 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5726

European-Non Finnish (NFE) AF: 0.0000775 AC: 86 AN: 1110002

Other (OTH) AF: 0.0000831 AC: 5 AN: 60166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	-	Familial adenomatous polyposis 2 (6)
4	-	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	not specified (2)
-	1	-	Familial colorectal cancer type X (1)
1	-	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_noAF	Benign	-0.87
CADD	Benign	19
DANN	Benign	0.74
PhyloP100		-2.7
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: -2
DS_AL_spliceai		0.36		Position offset: 40

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

Other links and lift over

dbSNP: rs372673338; hg19: chr1-45797481; COSMIC: COSV58344781; COSMIC: COSV58344781;