Heterozygous variant c.2593C>T on APC gene

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Joined: Wed Apr 19, 2017 11:52 am

Heterozygous variant c.2593C>T on APC gene

Postby mpbser » Tue Aug 08, 2017 2:02 pm

My husband's Invitae Common Hereditary Cancers Panel came back with all normal/negative results except for the following --

Gene: APC
Variant: c.2593C>t (p.Pro865Ser)
Zygosity: heterozygous
Variant classification: uncertain significance

It looks like there are conflicting classifications of this variant depending on the lab that does the testing:


I really could not understand what the geneticist was talking about when she explained what a variant classification of uncertain significance means. I was able to understand a little more by reading https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/

However, I'm at a 3rd grade level when it comes to anything dealing with genetics. Does anyone have a simple explanation of what this finding means?

Thanks in advance!
Wife 4/17 Dx age 45
5/17 - Lap left hemi
5 x 4 x 1 cm
low grade
T3 N2b M1a
Stage IV A
lymph nodes: 9 of 54
8/17 Sub-total colectomy
2nd tumor 5.5 cm T1 N0
CEA: 1.4, 2.1, 1.5, 1.9, 1.9, 2.1, 2.1, 2.4, 1.7, 2.0
Lynch no; KRAS wild
Immunohistochemsistry: Normal MLH1, MSH2, MSH6, and PMS2
Tumor DNA variants: MTOR, APC, TP53
Liver left hepatectomy seg 4 1/31/18
5/18 NED

Posts: 1
Joined: Thu Dec 07, 2017 8:32 am

Re: Heterozygous variant c.2593C>T on APC gene

Postby zenmind » Thu Dec 07, 2017 9:11 am

I work for another genomics lab and I just came across your question while reporting this variant in another patient.

In general a variant of uncertain significance means - A variant in your DNA that alters the protein in some way, either an amino acid (unit of the protein) at a particular position is changed to another one (as is the case for the variant in question) or the structure of the protein is somehow altered. But we do not know or there is little evidence whether this change will affect what the protein is supposed to do i.e its function.

In case of this variant, it was found in your husband who appears to be affected with colon cancer diagnosed at 45 and also in another patient who came to our lab for testing. This patient is however unaffected with any cancer at age 60.

So it is possible that the variant is either not the cause of colon cancer in your husband: This could imply that his cancer may not be hereditary (if all known genes associated have been tested).
The variant is of low penetrance : Meaning that not all individuals who carry the variant will necessarily express its effects.

With regard to various labs giving it different labels on ClinVar, it is better to see the latest label and the evidence provided. With variants whose exact effect is currently unknown, only accumulating evidence either in individuals/patients or experimental evidence will help understand their significance..

Posts: 1838
Joined: Fri Jul 21, 2017 3:43 am

Re: Heterozygous variant c.2593C>T on APC gene

Postby NHMike » Thu Dec 07, 2017 12:32 pm

I also got a report of "two other variant of unknown significance:" in my Genomic Tumor Results" with the comment: "At this time, there is not enough research/evidence into these two additional variants for us to know how they contribute to disease or affect theraph."
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal

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