1-45329368-C-G

Position:

• chr1-45329368-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001048174.2(MUTYH):​c.1504G>C​(p.Asp502His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 3.03

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1588G>C	p.Asp530His	missense_variant	16/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1504G>C	p.Asp502His	missense_variant	16/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1588G>C	p.Asp530His	missense_variant	16/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1504G>C	p.Asp502His	missense_variant	16/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251494 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000464 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 530 of the MUTYH protein (p.Asp530His). This variant is present in population databases (rs147923905, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 186948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 26, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2022	The p.D530H variant (also known as c.1588G>C), located in coding exon 16 of the MUTYH gene, results from a G to C substitution at nucleotide position 1588. The aspartic acid at codon 530 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11092888, 23108399) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.91	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.037	D;T;D;T;D;T;D;D;D;D;D;.
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.055, 0.091, 0.069	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.60
MutPred		0.26		.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0491);.;
MVP		0.89
MPC		0.51
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.41

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: rs147923905; hg19: chr1-45795040;