1-45331694-C-G

Variant names:

• chr1-45331694-C-G
• rs876659232
• NM_001048174.2:c.1069G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_001048174.2(MUTYH):​c.1069G>C​(p.Ala357Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A357S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.93
• Publications: 3 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 47 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-45331694-C-G is Benign according to our data. Variant chr1-45331694-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 921363.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1069G>C	p.Ala357Pro	missense_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1069G>C	p.Ala357Pro	missense_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1657G>C		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:2

Jan 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 921363). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 385 of the MUTYH protein (p.Ala385Pro). -

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with proline at codon 385 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with proline at codon 385 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Nov 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A385P variant (also known as c.1153G>C), located in coding exon 12 of the MUTYH gene, results from a G to C substitution at nucleotide position 1153. The alanine at codon 385 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	.;.;.;.;.;T;.;.;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.51	.;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.079	D
MutationAssessor	Benign	-0.86	.;.;.;.;.;N;.;.;.;.
PhyloP100		1.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;B;B;.;B;.
Vest4		0.48
MutPred		0.61		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0357);.;
MVP		0.93
MPC		0.15
ClinPred		0.17	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.54
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs876659232; hg19: chr1-45797366;