Genetic Variant MUTYH:p.Pro432Leu (chr1-45331447-TG-CA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001048174.2(MUTYH):c.1211_1212delCAinsTG (p.Pro404Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P404A: Uncertain_significance (ClinVar VariationId 4113156, 1 star); p.P404L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2740970); p.P404= (synonymous): Likely_benign (ClinVar VariationId 4860472, 1 star); p.P404Q: Uncertain_significance (ClinVar VariationId 2131517, 2 stars); p.P404R: Uncertain_significance (ClinVar VariationId 4113157, 1 star)

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001048174.2 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.833

Publications

0 publications found

Variant links:

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: G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

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new If you want to explore the variant's impact on the transcript NM_001048174.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00473) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001048174.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
MUTYH NM_001128425.2	MANE Plus Clinical	c.1295_1296delCAinsTG p.Pro432Leu	missense	N/A	Prot: NP_001121897.1 UniProt: E5KP25
MUTYH NM_001048174.2	MANE Select	c.1211_1212delCAinsTG p.Pro404Leu	missense	N/A	Prot: NP_001041639.1 UniProt: Q9UIF7-6
MUTYH NM_012222.3		c.1286_1287delCAinsTG p.Pro429Leu	missense	N/A	Prot: NP_036354.1 UniProt: Q9UIF7-1E5KP26

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1295_1296delCAinsTGp.Pro432Leu

Exon rankN/A

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1211_1212delCAinsTGp.Pro404Leu

Exon rankN/A

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1286_1287delCAinsTGp.Pro429Leu

Exon rankN/A

missense

Prot: NP_036354.1UniProt: Q9UIF7-1

E5KP26

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
MUTYH ENST00000710952.2	MANE Plus Clinical	c.1295_1296delCAinsTG p.Pro432Leu	missense	N/A	Prot: ENSP00000518552.2 UniProt: E5KP25
MUTYH ENST00000456914.7	TSL:1MANE Select	c.1211_1212delCAinsTG p.Pro404Leu	missense	N/A	Prot: ENSP00000407590.2 UniProt: Q9UIF7-6
MUTYH ENST00000372098.7	TSL:1	c.1286_1287delCAinsTG p.Pro429Leu	missense	N/A	Prot: ENSP00000361170.3 UniProt: Q9UIF7-1

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1295_1296delCAinsTGp.Pro432Leu

Exon rankN/A

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1211_1212delCAinsTGp.Pro404Leu

Exon rankN/A

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1286_1287delCAinsTGp.Pro429Leu

Exon rankN/A

missense

Prot: ENSP00000361170.3UniProt: Q9UIF7-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.83

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence