1-45331528-CG-TA

Variant names:

• chr1-45331528-CG-TA
• NM_001128425.2:c.1214_1215delCGinsTA
• MUTYH p.Pro405Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1_SupportingPM2PM5

The NM_001048174.2(MUTYH):c.1130_1131delCGinsTA (p.Pro377Leu) 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. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P377R: Likely_pathogenic (ClinVar VariationId 3914955, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P377= (synonymous): Likely_benign (ClinVar VariationId 232703, 2 stars); p.P377= (synonymous): Likely_benign (ClinVar VariationId 2065560, 2 stars); p.P377= (synonymous): Benign/Likely_benign (ClinVar VariationId 414158, 2 stars); p.P377S: Uncertain_significance (ClinVar VariationId 5298, 1 star); p.P377dup: Uncertain_significance (ClinVar VariationId 464679, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 0 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: 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

ENSG00000288208 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 11 benign (OR vs. background: 2.4).
	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.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.P377R: Likely_pathogenic (ClinVar VariationId 3914955, 1 star); Other variants at the same amino acid residue (not pathogenic): p.P377= (synonymous): Likely_benign (ClinVar VariationId 232703, 2 stars); p.P377= (synonymous): Likely_benign (ClinVar VariationId 2065560, 2 stars); p.P377= (synonymous): Benign/Likely_benign (ClinVar VariationId 414158, 2 stars); p.P377S: Uncertain_significance (ClinVar VariationId 5298, 1 star); p.P377dup: Uncertain_significance (ClinVar VariationId 464679, 2 stars)

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MUTYH NM_001128425.2	MANE Plus Clinical	c.1214_1215delCGinsTA p.Pro405Leu	missense	N/A	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001048174.2	MANE Select	c.1130_1131delCGinsTA p.Pro377Leu	missense	N/A	Prot: NP_001041639.1 UniProt:
	MUTYH NM_012222.3		c.1205_1206delCGinsTA p.Pro402Leu	missense	N/A	Prot: NP_036354.1 UniProt:

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1214_1215delCGinsTAp.Pro405Leu

Exon rankN/A

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1130_1131delCGinsTAp.Pro377Leu

Exon rankN/A

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1205_1206delCGinsTAp.Pro402Leu

Exon rankN/A

missense

Prot: NP_036354.1UniProt: Q9UIF7-1E5KP26

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MUTYH ENST00000710952.2	MANE Plus Clinical	c.1214_1215delCGinsTA p.Pro405Leu	missense	N/A	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000456914.7	TSL:1MANE Select	c.1130_1131delCGinsTA p.Pro377Leu	missense	N/A	Prot: ENSP00000407590.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.1205_1206delCGinsTA p.Pro402Leu	missense	N/A	Prot: ENSP00000361170.3 UniProt:

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1214_1215delCGinsTAp.Pro405Leu

Exon rankN/A

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1130_1131delCGinsTAp.Pro377Leu

Exon rankN/A

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1205_1206delCGinsTAp.Pro402Leu

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	Uncertain	7.2

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.

Other links and lift over

hg19: chr1-45797200;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar