Submissions for variant NM_001048174.2(MUTYH):c.487C>T (p.Arg163Trp)

dbSNP: rs761101420

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165580	SCV000216314	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The p.R191W variant (also known as c.571C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, designated as p.Arg177Trp, was detected in a Spanish patient diagnosed at age 29 with left-sided colon cancer but with no associated polyps (Riegert-Johnson DL et al. Genet Test, 2007;11:361-5). This alteration was also identified in a cohort of 882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci., 2020 Feb;111:647-657). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204489	SCV000262259	uncertain significance	Familial adenomatous polyposis 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MUTYH protein (p.Arg191Trp). This variant is present in population databases (rs761101420, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or personal or family history of hereditary breast and ovarian cancer (PMID: 18294051, 31742824). This variant is also known as p.Arg177Trp. ClinVar contains an entry for this variant (Variation ID: 186056). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000165580	SCV000685644	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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.
Counsyl	RCV000204489	SCV000797302	uncertain significance	Familial adenomatous polyposis 2	2018-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001594862	SCV001829302	uncertain significance	not provided	2021-11-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family history of breast and/or ovarian cancer (Shao 2020); This variant is associated with the following publications: (PMID: 18294051, 31742824)
Sema4, Sema4	RCV000165580	SCV002532300	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000204489	SCV002579583	uncertain significance	Familial adenomatous polyposis 2	2021-12-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000204489	SCV004198871	uncertain significance	Familial adenomatous polyposis 2	2023-09-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479037	SCV004223177	uncertain significance	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571C>T has been reported in the literature in heterozygous individuals affected with colorectal cancer without associated polyps, cardiac dysfunction, and increased risk of hereditary breast and ovarian cancer (e.g. Riegert-Johnson_2007, Lam_2015, Shao_2020). These reports 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: 28491533, 18294051, 31742824). Seven 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.
All of Us Research Program, National Institutes of Health	RCV000204489	SCV004837290	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 191 of the MUTYH protein. This variant is also known as NM_001048171.1:c.529C>T (p.Arg177Trp) in the literature. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 18294051) or breast cancer (PMID: 31742824, 33471991). In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 3/251480 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.
GenomeConnect - Invitae Patient Insights Network	RCV000204489	SCV001749674	not provided	Familial adenomatous polyposis 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-18-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.