rs140118273

Variant names:

• chr1-45329412-G-A
• rs140118273
• NM_001128425.2:c.1544C>T
• MUTYH p.Ser515Phe

Your query was ambiguous. Multiple possible variants found:

• chr1-45329412-G-A
• chr1-45329412-G-T
• chr1-45329412-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-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). BS1BS2BP4BP6_Strong

The NM_001048174.2(MUTYH):c.1460C>T (p.Ser487Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0111 (AC=17,856) in the gnomAD database across 1,614,140 control chromosomes, including 152 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0477. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S487A: Uncertain_significance (ClinVar VariationId 4113347, 1 star); p.S487P: Uncertain_significance (ClinVar VariationId 4113346, 1 star); p.S487= (synonymous): Likely_benign (ClinVar VariationId 3233029, 1 star); p.S487T: Likely_benign (ClinVar VariationId 4113345, 1 star); p.S487Y: Uncertain_significance (ClinVar VariationId 3073893, 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 0.0098 (12 hom., cov: 31)
  • Exomes 𝑓: 0.011 (140 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: 1.76
• Publications: 47 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: Benign. The variant received -13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (27/27 total B/LB).
	BS1Allele frequency higher than expected		GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0477 vs gene BS1 threshold 0.015.
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 152.; Very high cumulative gnomAD AC = 17856 (any gene).

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.1544C>T p.Ser515Phe	missense	Exon 16 of 16	Prot: NP_001121897.1 UniProt:
	MUTYH NM_001048174.2	MANE Select	c.1460C>T p.Ser487Phe	missense	Exon 16 of 16	Prot: NP_001041639.1 UniProt:
	MUTYH NM_012222.3		c.1535C>T p.Ser512Phe	missense	Exon 16 of 16	Prot: NP_036354.1 UniProt:

MUTYH NM_001128425.2

MANE Plus Clinical

HGVSc / HGVSpc.1544C>Tp.Ser515Phe

Exon rankExon 16 of 16

missense

Prot: NP_001121897.1UniProt: E5KP25

MUTYH NM_001048174.2

MANE Select

HGVSc / HGVSpc.1460C>Tp.Ser487Phe

Exon rankExon 16 of 16

missense

Prot: NP_001041639.1UniProt: Q9UIF7-6

MUTYH NM_012222.3

HGVSc / HGVSpc.1535C>Tp.Ser512Phe

Exon rankExon 16 of 16

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.1544C>T p.Ser515Phe	missense	Exon 16 of 16	Prot: ENSP00000518552.2 UniProt:
	MUTYH ENST00000456914.7	TSL:1MANE Select	c.1460C>T p.Ser487Phe	missense	Exon 16 of 16	Prot: ENSP00000407590.2 UniProt:
	MUTYH ENST00000372098.7	TSL:1	c.1535C>T p.Ser512Phe	missense	Exon 16 of 16	Prot: ENSP00000361170.3 UniProt:

MUTYH ENST00000710952.2

MANE Plus Clinical

HGVSc / HGVSpc.1544C>Tp.Ser515Phe

Exon rankExon 16 of 16

missense

Prot: ENSP00000518552.2UniProt: E5KP25

MUTYH ENST00000456914.7

TSL:1MANE Select

HGVSc / HGVSpc.1460C>Tp.Ser487Phe

Exon rankExon 16 of 16

missense

Prot: ENSP00000407590.2UniProt: Q9UIF7-6

MUTYH ENST00000372098.7

TSL:1

HGVSc / HGVSpc.1535C>Tp.Ser512Phe

Exon rankExon 16 of 16

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00977	AC:1487	Hom:12	AN:152146	Cov:31
GnomAD2 exomes	AF: 0.00841	AC:2115	Hom:	AN:251444	Cov:
GnomAD4 exome	AF: 0.0112	AC:16371	Hom:140	AN:1461876	Cov:31
GnomAD4 genome	AF: 0.00975	AC:1485	Hom:12	AN:152264	Cov:31
TOPMed (Bravo)	AF: 0.0106	AC:2795	Hom:23	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0110	AC:4503	Hom:32	AN:411060	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0141	AC:33	Hom:2	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0100	AC:3	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0111	AC:144	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00346	AC:12	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.104	AC:206	Hom:	AN:1974	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122084	Cov:
Turkish Variome	AF: 0.0119	AC:80	Hom:2	AN:6722	Cov:
UK10K	AF: 0.0110	AC:83	Hom:	AN:7562	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0107 *	119	11112	0.0109 *	192	17618
BipEx(Bipolar disorder (including schizoaffective))	0.0109	311	28420	0.0112	322	28844
Epi25(Epilepsy)	0.0104	435	41958	0.0113	757	66888
SCHEMA(Schizophrenia)	0.0143	1742	122124	0.0168	3233	191992

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

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (12)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	5	not provided (5)
-	-	4	Familial adenomatous polyposis 2 (4)
-	-	1	Familial multiple polyposis syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
GPN-Star LLR	N/A	-2.7
GPN-Star score	N/A	2.7
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
Mutation Taster	N/A	99/1	polymorphism
MutationAssessor	Benign	1.1	L
PhyloP100	Benign	1.8
popEVE	Benign	-3.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.034	D
Varity_R	N/A	0.041
VESM-3B	Benign	-6.0

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.080
SpliceAI score (max)	Benign	0.0	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.

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

dbSNP: rs140118273;

hg19: chr1-45795084;

COSMIC: COSV58344455;

COSMIC: COSV58344455;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar