Submissions for variant NM_001048174.2(MUTYH):c.796C>T (p.Arg266Cys)

gnomAD frequency: 0.00001  dbSNP: rs199840380

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160755	SCV000211409	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast cancer, but also in unaffected controls (PMID: 28135048, 33785725, 33471991); This variant is associated with the following publications: (PMID: 28135048, 28135145, 31159747, 32980694, 33785725, 36577833, 11092888, 11160897, 33471991, 31273614, 36243179)
Ambry Genetics	RCV000214420	SCV000274835	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-29	criteria provided, single submitter	clinical testing	The p.R294C variant (also known as c.880C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 880. The arginine at codon 294 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Liu X et al. Cancer Med. 2017 Mar;6:547-554; Gervas P et al. Exp Oncol, 2021 Mar;43:52-55). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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	RCV000459211	SCV000545786	uncertain significance	Familial adenomatous polyposis 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 294 of the MUTYH protein (p.Arg294Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 28135048, 33785725). ClinVar contains an entry for this variant (Variation ID: 182692). 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	RCV000214420	SCV000685677	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 294 of the MUTYH protein. This variant is known as c.838C>T (p.Arg280Cys) based on the alternate NM_001048171.1 transcript. Computational prediction tool 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: 28135145), breast cancer (PMID: 28135048, 33785725, 33471991), and an individual referred for hereditary screening (PMID: 31159747). This variant has been identified in 7/245982 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	RCV000459211	SCV000793524	uncertain significance	Familial adenomatous polyposis 2	2017-08-24	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000214420	SCV000822080	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160755	SCV001147267	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797643	SCV002041620	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.880C>T (p.Arg294Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251064 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.880C>T has been reported in the literature in settings of multigene panel testing among individuals affected with breast cancer (example, Liu_2017, Tsaousis_2019, Gervas_2019 and 2021) or with colorectal cancer (example, Yurgelun_2017). It has also been reported in both breast cancer and control cohorts (example, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8208_8209insAG, p.Leu2737fs) (Gervas_2019). 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: 33785725, 31273614, 28135048, 31159747, 28135145, 33471991). Eight 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.
Revvity Omics, Revvity	RCV000459211	SCV003817132	uncertain significance	Familial adenomatous polyposis 2	2021-10-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000459211	SCV004198839	uncertain significance	Familial adenomatous polyposis 2	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000459211	SCV004841031	uncertain significance	Familial adenomatous polyposis 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 294 of the MUTYH protein. This variant is known as c.838C>T (p.Arg280Cys) based on the alternate NM_001048171.1 transcript. Computational prediction tool 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: 28135145), breast cancer (PMID: 28135048, 33785725, 33471991), and an individual referred for hereditary screening (PMID: 31159747). This variant has been identified in 7/245982 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000160755	SCV005186674	uncertain significance	not provided		criteria provided, single submitter	not provided