1-45332167-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001048174.2(MUTYH):c.848G>A(p.Arg283Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001072
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:15
• Conservation: PhyloP100: 0.267

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03441319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.932G>A	p.Arg311Lys	missense_variant, splice_region_variant	10/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.848G>A	p.Arg283Lys	missense_variant, splice_region_variant	10/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.932G>A	p.Arg311Lys	missense_variant, splice_region_variant	10/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.848G>A	p.Arg283Lys	missense_variant, splice_region_variant	10/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251388 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135894

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000202

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: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.0000605 AC XY: 44 AN XY: 727246

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.000201

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: 0.0000369

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74492

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000700 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with lysine at codon 311 of the MUTYH protein. This variant is also known as NM_001048171.1:c.890G>A (p.Arg297Lys) in the literature. 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 been observed in individuals affected with colon, ovarian, breast and lung cancer (PMID: 25186627, 26689913, 27978560, 33471991, 35668106) as well as in an individual potentially biallelic and affected with MUTYH-associated polyposis (PMID: 34704405). This variant has been identified in 36/282768 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 311 of the MUTYH protein (p.Arg311Lys). This variant is present in population databases (rs149342980, gnomAD 0.08%). This missense change has been observed in individual(s) with ovarian, breast, colon cancer and colorectal polyposis (PMID: 25186627, 26689913, 27978560, 35264596). This variant is also known as c.890G>A (p.Arg297Lys). ClinVar contains an entry for this variant (Variation ID: 182694). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Revvity Omics, Revvity	Jun 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2016	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Observed in individuals with ovarian, lung, breast, or colon cancer (Lu 2015, Tung 2015, Pearlman 2017); Observed with a pathogenic MUTYH variant, phase (cis or trans) unknown, in a patient with suspected MUTYH-associated polyposis, however other variants of uncertain significance in MUTYH and other genes were also identified in this patient (Dell'Elice 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Arg297Lys; This variant is associated with the following publications: (PMID: 26689913, 27978560, 25186627, 11092888, 11160897, 16879101, 20816984, 34704405) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 13, 2023	In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMIDs: 35668106 (2022), 27978560 (2016)), breast cancer (PMID: 25186627 (2015)), and ovarian cancer or lung cancer (PMID: 26689913 (2015)). The frequency of this variant in the general population, 0.0008 (20/24940 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2022	The p.R311K variant (also known as c.932G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 932. The arginine at codon 311 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with ovarian cancer from a cohort of 4034 individuals with cancer undergoing whole exome sequencing (Lu C et al. Nat. Commun. 2015 Dec;6:10086). This variant was observed in an individual diagnosed with breast cancer greater than age 50 and was considered low-risk based on family history (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in a female proband diagnosed at age 37 with colon cancer and in a female proband diagnosed with colorectal cancer in her 60s, but no co-occurring pathogenic variants in MUTYH were reported for either patient (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Georgeson P et al. Nat Commun, 2022 06;13:3254). This amino acid position is not well conserved in available vertebrate species, and lysine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 12, 2022	This missense variant replaces arginine with lysine at codon 311 of the MUTYH protein. This variant is also known as NM_001048171.1:c.890G>A (p.Arg297Lys) in the literature. 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 been observed in individuals affected with colon, ovarian, breast and lung cancer (PMID: 25186627, 26689913, 27978560, 33471991, 35668106) as well as in an individual potentially biallelic and affected with MUTYH-associated polyposis (PMID: 34704405). This variant has been identified in 36/282768 chromosomes 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 13, 2023

Variant summary: MUTYH c.932G>A (p.Arg311Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251388 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.932G>A has been reported in the literature in individuals affected with different types of cancers including Colorectal Cancer, Pancreatic Cancer, Breast Cancer and other unspecified cancer (example, Tung_2015, Lu_2015, Pearlman_2016, Zhu_2021, Guindalini_2022, Bhai_2021). It has also been reported in both case and control cohorts of a large case-control study of Breast Cancer (Dorling_2021. 3/60466 cases vs 5/53461 controls). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 35264596, 26689913, 27978560, 25186627, 33939675, 33471991). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Benign	0.84
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.44	N;N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.24
Sift	Benign	0.34	T;T;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;B;B;.;B;.;.
Vest4		0.26
MVP		0.88
MPC		0.11
ClinPred		0.0034	T
GERP RS		1.7
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.020
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: rs149342980; hg19: chr1-45797839;