Submissions for variant NM_001040108.2(MLH3):c.3217G>A (p.Asp1073Asn)

gnomAD frequency: 0.00551  dbSNP: rs28756993

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001115200	SCV000562025	benign	Colorectal cancer, hereditary nonpolyposis, type 7	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001115200	SCV001273159	likely benign	Colorectal cancer, hereditary nonpolyposis, type 7	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001357519	SCV002551425	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001357519	SCV002612195	benign	not specified	2020-06-24	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001115200	SCV004015901	benign	Colorectal cancer, hereditary nonpolyposis, type 7	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004705614	SCV005212592	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357519	SCV001553012	benign	not specified		no assertion criteria provided	clinical testing	The MLH3 p.Asp1073Asn variant was identified in 9 of 2462 proband chromosomes (frequency: 0.0037) from individuals with colorectal cancer and was not identified in 186 control chromosomes from healthy individuals (DeRycke_2017_PMID:28944238). The variant was identified in dbSNP (ID: rs28756993), ClinVar (classified as benign by Invitae) and LOVD 3.0 (classified as a variant of uncertain significance by InSiGHT); the variant was not identified in Cosmic. The variant was identified in control databases in 510 of 268318 chromosomes (1 homozygous) at a frequency of 0.001901 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: African in 403 of 23614 chromosomes (freq: 0.01707), Latino in 79 of 35098 chromosomes (freq: 0.002251), Other in 5 of 6698 chromosomes (freq: 0.000747), European (non-Finnish) in 21 of 118176 chromosomes (freq: 0.000178), Ashkenazi Jewish in 1 of 9862 chromosomes (freq: 0.000101) and South Asian in 1 of 30524 chromosomes (freq: 0.000033), but was not observed in the East Asian or European (Finnish) populations. The p.Asp1073 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 this variant meets our laboratory's criteria to be classified as benign.