Submissions for variant NM_000038.6(APC):c.5879_5880delinsTA (p.Pro1960Leu)

dbSNP: rs587779801

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115107	SCV000149016	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; While this variant has not been previously reported as pathogenic or benign to our knowledge, another variant resulting in the same amino acid substitution, APC c.5879C>T, has been reported in at least two individuals with colon cancer (Pearlman et al., 2017; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 27978560, 28135145, 18199528)
Invitae	RCV003534341	SCV000282785	uncertain significance	Familial adenomatous polyposis 1	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1960 of the APC protein (p.Pro1960Leu). This variant is present in population databases (rs587779801, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560, 28135145). ClinVar contains an entry for this variant (Variation ID: 127309). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Counsyl	RCV000232068	SCV000488890	uncertain significance	Familial adenomatous polyposis 1	2016-07-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491906	SCV000579869	likely benign	Hereditary cancer-predisposing syndrome	2021-01-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000491906	SCV000681766	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This variant replaces proline with leucine at codon 1960 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A different DNA change with the same protein effect, c.5879C>T (p.Pro1960Leu), has been reported in individuals affected with colon cancer (PMID: 27978560, 28135145). This variant has also been identified in 9/282040 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	RCV000115107	SCV000888751	uncertain significance	not provided	2019-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255490	SCV001431916	uncertain significance	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.5879_5880delinsTA (p.Pro1960Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282224 control chromosomes (gnomAD). However, it has been reported in the database as two separate single nucleotide changes: 5-112177170-C-T (missense) and 5-112177171-G-A (synonymous polymorphism). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5879_5880delinsTA in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.