Submissions for variant NM_001048174.2(MUTYH):c.1174C>A (p.Leu392Met)

gnomAD frequency: 0.00041  dbSNP: rs144079536

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034669	SCV000149664	likely benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with colorectal and other cancers (Peterlongo 2006, Olschwang 2007, Smith 2009, Guarinos 2014, Ballinger 2016, Jalkh 2017, Ricci 2017, Scarpa 2017, Rizzolo 2018); Observed with an intronic MUTYH variant in an individual with suspected MUTYH-associated polyposis (MAP), phase unknown (Ricci 2017); Published functional studies demonstrate no damaging effect: spontaneous mutation rates similar to wild type in an E. coli-based complementation assay (Komine 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24470512, 25503501, 28873162, 30564557, 25820570, 29700634, 21777424, 22703879, 20110747, 16774938, 18515411, 27829682, 17949294, 26632267, 28199314, 26269718, 27498913, 28717660, 28202063, 21153778, 19725997, 28526081, 21287799, 30374176, 26689913, 26580448)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123143	SCV000166446	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115755	SCV000187241	benign	Hereditary cancer-predisposing syndrome	2014-06-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Vantari Genetics	RCV000115755	SCV000267060	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-25	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115755	SCV000679735	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212714	SCV000697673	benign	not specified	2021-01-01	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1258C>A (p.Leu420Met) results in a conservative amino acid change located in the NUDIX hydrolase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 251380 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00059 vs 0.0046), allowing no conclusion about variant significance. c.1258C>A has been reported in the literature in sequencing studies among individuals affected with MUTYH-associated Polyposis, a variety of other cancer types and in unaffected controls (example, Cabanillas_2017, Cheng_2017, Guarinos_2014, Jalkh_2017, Johnston_2012, Maxwell_2015, Olschwang_2007, Peterlongo_2006, Ricci_2016, Rosner_2010, Smith_2009, Zhang_2015, Singal_2017, Ackay_2021, Rizzolo_2018, Tsai_2019). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an assay evaluating base excision repair (BER) with a MutY-Deficient E Coli complementation assay (Komine_2015). Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=9; benign/likely benign, n=4). Some submitters cite overlapping literature utilized in the context of our evaluation. Our laboratory, among others previously re-classified this variant from uncertain significance to likely benign. Its latest re-evaluation spanning a comprehensive review of published evidence still does not point to a concrete actionable outcome and the overall directionality of evidence seems to support a benign outcome. Based on all the evidence outlined above, the variant was re-classified as benign.
Mendelics	RCV000123143	SCV000837750	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000123143	SCV000886461	likely benign	Familial adenomatous polyposis 2	2018-05-17	criteria provided, single submitter	research	The MUTYH variant designated as NM_001128425.1:c.1258C>A (p.Leu420Met, historically known as p.Leu417Met) was previously classified as a variant of uncertain significance and is now classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 900 individuals with European ancestry. This population frequency is not consistent with the frequency of pathogenic mutations in MUTYH. This variant is a missense variant and pathogenic variants in MUTYH are most frequently truncating variants. This variant has been classified as likely benign and benign by other laboratories (ClinVar Variation ID: 41752). Together, this information is consistent with a likely benign variant in MUTYH. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MUTYH function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health	RCV000115755	SCV000910570	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123143	SCV001253577	uncertain significance	Familial adenomatous polyposis 2	2018-09-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034669	SCV001470026	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 27829682 (2016), 24470512 (2014), 21287799 (2010), 17949294 (2007), 16774938 (2006)), breast cancer (PMID: 32658311 (2021), 30564557 (2018), 29700634 (2018), 28202063 (2017), 25503501 (2015)), ovarian cancer (PMID: 33558524 (2021), 26689913 (2015)), pancreatic cancer (PMID: 20110747 (2009)), and gastric cancer (PMID: 32066632 (2021)). In a large-scale breast cancer association study, this variant was reported in individuals with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). A functional study in bacteria showed this variant does not affect MUTYH DNA damage repair activity (PMID: 25820570 (2015)). The frequency of this variant in the general population, 0.0022 (23/10364 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034669	SCV002011070	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115755	SCV002532217	likely benign	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212714	SCV002552429	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000034669	SCV004847559	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing	The p.Leu420Met variant in MUTYH has been reported in 4 individuals with colorectal cancer (Peterlongo 2006 - variant reported as Leu406Met, Ricci 2016), one of whom carried a second intronic variant in MUTYH, although phase was not known. Functional studies in bacteria (E.coli) suggest that the p.Leu420Met variant may not impact protein function (Komine 2015). However, these types of assays may not accurately represent biological function. This variant has been identified in 16/16506 South Asian chromosomes (0.1%) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144079536). This frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein although 1 mammal (Pika) has the variant amino acid (Met) at this position. In summary, while the clinical significance of the p.Leu420Met variant is uncertain, these data suggest that it is more likely to be benign.
CeGaT Center for Human Genetics Tuebingen	RCV000034669	SCV005051663	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034669	SCV000043369	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000123143	SCV000503542	uncertain significance	Familial adenomatous polyposis 2	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 36 year old with a history of 2 colon polyps and a family history of colon cancer.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353918	SCV000592714	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Leu420Met variant was identified in 2 of 1084 proband chromosomes (frequency: 0.002) from individuals or families with MMR negative colon cancer or MUTYH-associated polyposis (Peterlongo 2006, Guarinos 2014). The variant was also present in 1 of 1096 chromosomes (frequency: 0.001) from individuals with atherosclerosis phenotypes with who underwent secondary variant detection (Johnston 2012). In a functional E. coli-based complementation assay, the variant retained functional expression, showing spontaneous mutation rates similar to wild type (Komine 2015). The variant was identified in dbSNP (ID: rs144079536) "With Uncertain significance, other allele", and ClinVar (classified with conflicting interpretations of pathogenicity: benign by Ambry Genetics and Color; likley benign by Invitae and two other laboratories; and uncertain significance by GeneDx and eight other laboratories). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 151 (1 homozygous) of 276982 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 24014 chromosomes (freq: 0.0001), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 19 of 34416 chromosomes (freq: 0.0006), European Non-Finnish in 77 of 126584 chromosomes (freq: 0.0006), Ashkenazi Jewish in 20 (1 homozygous) of 10150 chromosomes (freq: 0.002), and South Asian in 28 of 30778 chromosomes (freq: 0.0009) while not observed in the East Asian and European Finnish populations. The variant was also identified by our laboratory in 1 individual with ovarian cancer, co-occurring with a pathogenic APC variant (c.-85-?_1408+?del/deletion of Promoter 1A/1B, exons 1 to 10) increasing the likelihood the variant has little clinical significance. The p.Leu420 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Met impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics	RCV000115755	SCV000788061	uncertain significance	Hereditary cancer-predisposing syndrome	2017-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528162	SCV000806340	likely benign	MUTYH-related disorder	2023-06-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center of Medical Genetics and Primary Health Care	RCV000115755	SCV000987279	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A domain DNA_Glycosylase_C (R354-483Y aa) involved in Adenine DNA glycosylation. Hot-spot has 24 non-VUS coding variants (12 PATH and 12 BEN), pathogenicity = 50.0%, proximity score 3.836 > threshold 2.472. PP2 Pathogenic Supporting: 59 out of 97 non-VUS missense variants in gene MUTYH are PATH = 60.8% > threshold of 51.0%, and 191 out of 1,184 clinically reported variants in gene MUTYH are PATH = 16.1% > threshold of 12.0%. PP3 Pathogenic Supporting: 7 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 4 benign predictions from DEOGEN2, EIGEN, PrimateAI and REVEL. PP4 Pathogenic Supporting: The variant was detected in two unrelated female patients diagnosed with bilateral breast cancer or breast and ovarian cancers both with strong family history of breast and ovarian cancer. BS3 Benign Strong: At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an assay evaluating base excision repair (BER) with a MutY-Deficient E Coli complementation assay (PMID: 25820570). 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.