rs138089183

Variant names:

• chr1-45332174-G-A
• rs138089183
• NM_001128425.2:c.925C>T
• MUTYH p.Arg309Cys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). BP6

The NM_001048174.2(MUTYH):c.841C>T (p.Arg281Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000694 (AC=1,121) in the gnomAD database across 1,614,204 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000837. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R281H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 142801); p.R281L: Uncertain_significance (ClinVar VariationId 1051784, 2 stars); p.R281= (synonymous): Likely_benign (ClinVar VariationId 2033035, 1 star); p.R281S: Uncertain_significance (ClinVar VariationId 4113910, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20 B:6 O:1
• Conservation: PhyloP100: -0.212
• Publications: 45 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: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.925C>T	p.Arg309Cys	missense	Exon 10 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.841C>T	p.Arg281Cys	missense	Exon 10 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.916C>T	p.Arg306Cys	missense	Exon 10 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.925C>T	p.Arg309Cys	missense	Exon 10 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.841C>T	p.Arg281Cys	missense	Exon 10 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.916C>T	p.Arg306Cys	missense	Exon 10 of 16	ENSP00000361170.3	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000466	AC:71	Hom:0	AN:152206	Cov:33
GnomAD2 exomes	AF: 0.000454	AC:114	Hom:	AN:251334	Cov:
GnomAD4 exome	AF: 0.000718	AC:1050	Hom:1	AN:1461880	Cov:36
GnomAD4 genome	AF: 0.000466	AC:71	Hom:0	AN:152324	Cov:33
TOPMed (Bravo)	AF: 0.000431	AC:114	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000631	AC:209	Hom:1	AN:331342	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000538	AC:7	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Turkish Variome	AF: 0.000359	AC:2	Hom:0	AN:5100	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000630 *	7	11108	0.00142 *	25	17614
BipEx(Bipolar disorder (including schizoaffective))	0.000704	20	28420	0.000763	22	28844
Epi25(Epilepsy)	0.000596	25	41958	0.000508	34	66888
SCHEMA(Schizophrenia)	0.000314	33	105080	0.000278	41	147522

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	2	Familial adenomatous polyposis 2 (8)
-	6	1	not provided (7)
-	2	2	Hereditary cancer-predisposing syndrome (4)
-	3	-	not specified (3)
-	1	-	Familial colorectal cancer type X (1)
-	1	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)
-	-	1	Hereditary cancer (1)
-	1	-	MUTYH-related disorder (1)
-	1	-	Pilocytic astrocytoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.3
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.031	N
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.060	T
MetaSVM	Uncertain	-0.042	T
Mutation Taster	N/A	0/100	disease causing
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	-0.21
popEVE	Benign	-3.1
PrimateAI	Benign	0.20	T
PromoterAI	N/A	0.025	Neutral
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Varity_R	N/A	0.13
VESM-3B	Benign	-7.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs138089183;

hg19: chr1-45797846;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar