ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1174C>A (p.Leu392Met) (rs144079536)

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Total submissions: 17
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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)
Invitae RCV000123143 SCV000166446 benign MYH-associated polyposis 2020-12-07 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: 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.
PreventionGenetics,PreventionGenetics RCV000034669 SCV000806340 uncertain significance not provided 2017-03-09 criteria provided, single submitter clinical testing
Mendelics RCV000123143 SCV000837750 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000123143 SCV000886461 likely benign MYH-associated polyposis 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 Health, Inc RCV000115755 SCV000910570 benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123143 SCV001253577 uncertain significance MYH-associated polyposis 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 2020-03-19 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 MYH-associated polyposis 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
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.

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