Submissions for variant NM_000179.3(MSH6):c.2555AGA[2] (p.Lys854del)

dbSNP: rs587782858

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132477	SCV000187571	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-03	criteria provided, single submitter	clinical testing	The c.2561_2563delAGA variant (also known as p.K854del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 2561 to 2563, causing the removal of a lysine residue at codon 854. This alteration has been reported in a French patient with a clinical diagnosis of Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in conjunction with a known MSH6 pathogenic mutation; however, authors note that the clinical presentation is more consistent with an early form of Lynch syndrome than with CMMRD, suggesting that this alteration may not be completely inactivating (Bougeard G et al. Fam. Cancer. 2014 Mar;13:131-5; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been identified in several individuals with Lynch-associated tumors that were microsatellite stable (MSS) and/or had normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226221	SCV000283756	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This variant, c.2561_2563del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys854del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751683437, gnomAD 0.004%). This variant has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and breast cancer and clinical features of Lynch syndrome (PMID: 25186627, 26318770, 32547938; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 142970). 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.
GeneDx	RCV000656896	SCV000565226	uncertain significance	not provided	2023-09-23	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Observed with a pathogenic MSH6 variant on the opposite allele (in trans) in a case of possible constitutional mismatch repair deficiency (CMMR-D), but analysis of all mismatch repair genes was not performed and therefore this variant may not be responsible for the phenotype (Bougeard et al., 2014); Observed in individuals with breast cancer (Tung et al., 2015; Nikitin et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Located in the critical Lever domain (Warren et al., 2007; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 29596542, 30877237, 26318770, 26116798, 29755653, 17531815, 21120944, 30702970, 32547938, 35752529, 25186627, 24068316)
Color Diagnostics, LLC DBA Color Health	RCV000132477	SCV000685296	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	This variant causes a deletion of 1 amino acid from the MSH6 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with a pathogenic frameshift mutation in an individual affected with early-onset Lynch syndrome (PMID: 24068316, 26318770). This variant has also been observed as a somatic variant in a tumor sample from in an individual affected with Lynch syndrome, who carried a pathogenic MSH2 mutation (inversion of exons 1 - 7 inversion, also known as Boland mutation) in the germline (PMID: 29755653). This variant has been identified in 5/249108 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656896	SCV000888259	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	The MSH6 c.2561_2563del (p.Lys854del) variant has been reported in the published literature in trans with a pathogenic MSH6 variant in an individual with suspected constitutional mismatch repair deficiency (CMMRD), however inconsistencies in tumor features and clinical presentation led to reported classification of p.Lys854del as a variant of uncertain significance in this context (PMID: 26318770 (2015), 26116798 (2015), 24068316 (2014)). This variant has also been reported in an individual with breast cancer (PMID: 25186627 (2015)). The frequency of this variant in the general population, 0.000036 (4/112662 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202234	SCV001437241	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2561_2563delAGA (p.Lys854del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2561_2563delAGA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or breast cancer (Bougeard_2014, Gray_2018, Hampel_2018, Nikitin_2020, Salvador_2018, Tung_2014, Lin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant has been reported in a patient with Constitutional Mismatch Repair-Deficiency Syndrome (MSH6 c.3261dupC, p.Phe1088Leufs*5), providing supporting evidence for a benign role (Bodo_2015). 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: 26116798, 24068316, 29755653, 29596542, 35752529, 32547938, 30702970, 25186627). Six 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.
Sema4, Sema4	RCV000132477	SCV002535750	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	curation
Baylor Genetics	RCV003467198	SCV004195547	uncertain significance	Endometrial carcinoma	2024-03-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202234	SCV000257223	uncertain significance	not specified		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249963	SCV001423977	likely pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333737	SCV004041677	uncertain significance	Lynch syndrome 5	2023-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739464	SCV005350689	uncertain significance	MSH6-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The MSH6 c.2561_2563delAGA variant is predicted to result in an in-frame deletion (p.Lys854del). This variant was reported in several individuals with clinical features of Lynch syndrome or constitutional mismatch repair deficiency syndrome (Bougeard et al. 2014. PubMed ID: 24068316; Jensson et al. 2023. PubMed ID: 37937776; Tung et al. 2014. PubMed ID: 25186627; Salvador et al. 2019. PubMed ID: 30702970). This variant is reported in 0.0036% of alleles in individuals of European (non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142970/). Although we suspect this variant may be pathogenic, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.