ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3971_3973AGA[1] (p.Lys1325del) (rs587779300)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129067 SCV000183768 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410833 SCV000488119 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-31 criteria provided, single submitter clinical testing
Invitae RCV000627698 SCV000551049 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-06 criteria provided, single submitter clinical testing This variant, c.3974_3976delAGA, results in the deletion of 1 amino acid of the MSH6 protein (p.Lys1325del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with breast cancer (PMID: 26976419) and an individual with ovarian and endometrial cancer (PMID: 26648449). It has also been reported as homozygous in an individual with colorectal cancer who did not exhibit characteristics of congenital mismatch repair deficiency, and whose family history was not indicative of Lynch syndrome (PMID: 26437257). ClinVar contains an entry for this variant (Variation ID: 89494). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid 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 RCV000657124 SCV000569503 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in MSH6 is denoted c.3974_3976delAGA at the cDNA level and p.Lys1325del (K1325del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAGA[delAGA]TGAA. This variant was observed in at least one individual with breast cancer who had multi-gene cancer panel testing (Tung 2016). Additionally, this in-frame deletion was observed in the homozygous state in at least one individual with colorectal cancer, whose history was not suggestive of constitutional mismatch repair deficiency (CMMR-D). Of note, this patient's parents were consanguineous cousins and their family history was not suggestive of Lynch syndrome (Carneiro da Silva 2015). This variant was not observed in large population cohorts (Lek 2016). This deletion of a single Lysine amino acid is located in the ATPase domain and binding site of MSH2 (Kansikas 2011, Warren 2007, Kariola 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Lys1325del to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480251 SCV000601593 uncertain significance not specified 2017-02-08 criteria provided, single submitter clinical testing
Color RCV000129067 SCV000690424 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000074962 SCV000914312 uncertain significance Lynch syndrome 2019-01-30 criteria provided, single submitter research
Mendelics RCV000410833 SCV001135854 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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