Submissions for variant NM_000251.2(MSH2):c.38G>A (p.Ser13Asn) (rs63749907)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235367	SCV000292975	uncertain significance	not provided	2016-02-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.38G>A at the cDNA level, p.Ser13Asn (S13N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser13Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ser13Asn occurs at a position that is not conserved and is located within the mismatch binding domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Ser13Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000572196	SCV000676072	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-30	criteria provided, single submitter	clinical testing	Insufficient evidence;In silico models in agreement (benign)
Invitae	RCV000688689	SCV000816311	uncertain significance	Hereditary nonpolyposis colon cancer	2019-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 13 of the MSH2 protein (p.Ser13Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 245828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	RCV000572196	SCV001356786	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-12	criteria provided, single submitter	clinical testing

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