1-45332440-G-C

Variant names:

• chr1-45332440-G-C
• rs587782885
• NM_001128425.2:c.739C>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.655C>G​(p.Arg219Gly) 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: "SCV001218140: Experimental studies have shown that this missense change affects MUTYH function (PMID:26694661, 31285513)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.54
• Publications: 21 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001218140: Experimental studies have shown that this missense change affects MUTYH function (PMID: 26694661, 31285513).; SCV002673523: "In one study, this alteration demonstrated partially retained functional activity (Shinmura K et al. Hum. Mutat., 2016 Apr;37:350-3)."
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 48 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 1-45332440-G-C is Pathogenic according to our data. Variant chr1-45332440-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 587355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048174.2. 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.739C>G	p.Arg247Gly	missense	Exon 9 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.655C>G	p.Arg219Gly	missense	Exon 9 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.730C>G	p.Arg244Gly	missense	Exon 9 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.739C>G	p.Arg247Gly	missense	Exon 9 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.655C>G	p.Arg219Gly	missense	Exon 9 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.730C>G	p.Arg244Gly	missense	Exon 9 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial adenomatous polyposis 2 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.0091
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	0.93	L
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.033	D
Polyphen		0.19	B
Vest4		0.86
MutPred		0.68		Loss of methylation at R247 (P = 0.0143)
MVP		0.90
MPC		0.38
ClinPred		0.95	D
GERP RS		4.7
PromoterAI		-0.00060	Neutral
Varity_R		0.90
gMVP		0.81
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782885; hg19: chr1-45798112;