Submissions for variant NM_000249.4(MLH1):c.1500_1502del (p.Ile501del)

dbSNP: rs587778920

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000550597	SCV000625074	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing	This variant, c.1500_1502del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Ile501del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753409799, gnomAD 0.006%). This variant has been observed in individual(s) with an adrenocortical tumor and/or Lynch syndrome (PMID: 12095971, 28874130, 29520894, 32156018). This variant is also known as c.1499-1501delTCA. ClinVar contains an entry for this variant (Variation ID: 89755). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
PreventionGenetics, part of Exact Sciences	RCV000679268	SCV000805950	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000659872	SCV001136415	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011893	SCV001172275	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-14	criteria provided, single submitter	clinical testing	The c.1500_1502delCAT variant (also known as p.I501del) is located in coding exon 13 of the MLH1 gene. This variant results from an in-frame CAT deletion at nucleotide positions 1500 to 1502. This results in the in-frame deletion of an isoleucine at codon 501. This alteration has been reported in a Brazilian female with colorectal cancer at age 60 (Rossi BM et al. Ann Surg Oncol, 2002 Jul;9:555-61). This alteration was identified in an individual diagnosed with an adrenocortical tumor who also carries a TP53 mutation, Arg337His (Brondani VB et al. Cancers (Basel), 2020 Mar;12). This alteration was also detected once in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). Of note, this alteration is also designated as c.1499_1501delTCA in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001011893	SCV001357024	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-13	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of 1 amino acid of the MLH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant protein have wild-type expression level and DNA mismatch repair activity (PMID 29520894). This variant has been reported in 1 individual affected with Lynch Syndrome (PMID 29520894, 28874130). This variant has been identified in 3/251478 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.
Sema4, Sema4	RCV001011893	SCV002528657	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
GeneDx	RCV000679268	SCV004030650	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Located in the critical region of interaction with EXO1 and PMS2/MLH2/PMS1 (Plotz et al., 2003; Kosinski et al., 2010; Andersen et al., 2012); Published functional studies demonstrate no damaging effect: no significant effect on protein expression levels or mismatch repair activity (Kger et al., 2018); Observed in individuals with colorectal cancer or breast cancer, and co-observed with a pathogenic TP53 variant in a pediatric patient with adrenocortical neoplasm (Rossi et al., 2002; Brondani et al., 2020; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24344984, 12095971, 28874130, 22753075, 12799449, 20533529, 35264596, 29520894, 32156018)
All of Us Research Program, National Institutes of Health	RCV003997115	SCV004841027	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of 1 amino acid of the MLH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant protein have wild-type expression level and DNA mismatch repair activity (PMID 29520894). This variant has been reported in 1 individual affected with Lynch Syndrome (PMID 29520894, 28874130). This variant has been identified in 3/251478 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659872	SCV000781757	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	flagged submission	clinical testing