rs1060501335

Positions:

• chr1-45331684-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.1079T>C​(p.Leu360Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L360V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-45331684-A-G is Pathogenic according to our data. Variant chr1-45331684-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331684-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1163T>C	p.Leu388Pro	missense_variant	12/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1079T>C	p.Leu360Pro	missense_variant	12/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1163T>C	p.Leu388Pro	missense_variant	12/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1079T>C	p.Leu360Pro	missense_variant	12/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461720 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 388 of the MUTYH protein (p.Leu388Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenomatous polyposis (PMID: 16134147, 16941501, 17949294). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1121 T>C, p.Leu374Pro, and p.L360P. ClinVar contains an entry for this variant (Variation ID: 406845). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 20848659, 23322991, 25820570). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2021	Variant summary: MUTYH c.1163T>C (p.Leu388Pro) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250094 control chromosomes (gnomAD and publications). c.1163T>C has been reported in the literature in compound heterozygous individuals affected with MUTYH-Associated Polyposis (e.g. Aceto_2005, Lejeune_2006). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant severely impacts protein activity (e.g. Goto_2010, Shinmura_2012, Komine_2015). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2023	The p.L388P pathogenic mutation (also known as c.1163T>C), located in coding exon 12 of the MUTYH gene, results from a T to C substitution at nucleotide position 1163. The leucine at codon 388 is replaced by proline, an amino acid with similar properties. This alteration has been identified in one individual with approximately 40 colorectal adenomas in conjunction with a pathogenic founder mutation in MUTYH; the authors report this patient had no detectable APC mutation and that family studies confirmed these MUTYH alterations to be in trans, but did not provide further details (Aceto G et al. Hum. Mutat. 2005 Oct; 26(4):394). This alteration has been identified in several other individuals with multiple polyps; however, phase was not determined and specific clinical information including polyp count was not provided (Lejeune S et al. Hum. Mutat. 2006 Oct; 27(10):1064; Olschwang S et al. Genet. Test. 2007; 11(3):315-20). This alteration has also been detected in conjunction with another pathogenic mutation in MUTYH by our laboratory, but phase is unknown (Ambry internal data). Various functional assays designed to measure base excision repair function have found this alteration to result in a severely deficient protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74; Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42; Komine K et al. Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.L360P and p.L374P in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jul 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2020	This missense variant replaces leucine with proline at codon 388 of the MUTYH protein. This variant is also known as p.Leu360Pro and p.Leu374Pro based on alternate transcripts. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs DNA glycosylase activity (PMID: 20848659) and ability to suppress spontaneous mutation (PMID: 23322991, 25820570). This variant has been reported in compound heterozygosity with known pathogenic mutations in multiple individuals affected with adenomatous polyposis (PMID: 16134147, 16941501, 26511139). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2023

Published functional studies demonstrate a damaging effect: severely impaired glycosylase activity, base excision repair activity, and suppression of oxidative mutagenesis (Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015); Co-observed, phase unspecified, with a MUTYH nonsense variant in an individual with multiple colon polyps (Lejeune et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also reported as c.1121T>C p.Leu374Pro using nomenclature from the alternate transcript NM_001048171; This variant is associated with the following publications: (PMID: 23108399, 26511139, 25820570, 23605219, 21777424, 23507534, 25124163, 23322991, 20848659, 19725997, 17949294, 16134147, 16941501) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	.;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;.;.;.;.;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.
Vest4		0.97
MutPred		0.94		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0188);.;
MVP		0.99
MPC		0.70
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501335; hg19: chr1-45797356;