Submissions for variant NM_001048174.2(MUTYH):c.1318_1319del (p.Thr440fs)

dbSNP: rs1553125075

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561817	SCV000676153	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing	The c.1402_1403delAC pathogenic mutation, located in coding exon 14 of the MUTYH gene, results from a deletion of two nucleotides at nucleotide positions 1402 to 1403, causing a translational frameshift with a predicted alternate stop codon (p.T468Rfs*63). This truncating mutation was seen twice in conjunction with a second MUTYH pathogenic mutation (phase unknown) in two individuals with features of MUTYH-associated polyposis (MAP) (Ambry internal data). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000561817	SCV001344228	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This variant changes 2 nucleotides in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, 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). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377116	SCV001574352	likely pathogenic	Familial adenomatous polyposis 2	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr468Argfs*63) in the MUTYH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the MUTYH protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is also known as Gln512-Phe519. ClinVar contains an entry for this variant (Variation ID: 486917). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the conserved PCNA binding motif of the MUTYH protein, which has been shown to be critical for MUTYH-PCNA binding and repair efficiency (PMID: 11092888, 26377631, 11433026, 11864576). While functional studies have not been performed to directly test the effect of this variant on MUTYH protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV001377116	SCV004199418	likely pathogenic	Familial adenomatous polyposis 2	2022-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001377116	SCV004826475	pathogenic	Familial adenomatous polyposis 2	2023-10-02	criteria provided, single submitter	clinical testing	This variant changes 2 nucleotides in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, 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). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV004767411	SCV005378339	likely pathogenic	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 82 amino acids are replaced with 62 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23108399)