Analysis of genetic variants

Patent metadata

Field	Value
Publication number	US-9792403-B2
Application number	US-201414274525-A
Country	US
Kind code	B2
Filing date	May 9, 2014
Priority date	May 10, 2013
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Methods and systems for analyzing genetic variants are disclosed.

First claim

What is claimed is:

1. A method of characterizing a variant in a tumor sample from a subject as being a somatic or germline event, the method comprising:
a) sequencing each of a plurality of selected subgenomic intervals, each of a plurality of selected germline SNPs, and a variant, wherein the average sequence coverage prior to normalization is at least about 250×;
b) acquiring:
i) a sequence coverage input (SCI), which comprises, for each of the plurality of selected subgenomic intervals, a value for normalized sequence coverage at the selected subgenomic intervals, wherein SCI comprises a comparison of the number of reads for a subgenomic interval with the number of reads for a process-matched control;
ii) an SNP allele frequency input (SAFI), which comprises, for each of the plurality of selected germline SNPs, a value for a minor allele frequency in the tumor sample; and
iii) for said variant being characterized, a variant allele frequency input (VAFI), which comprises the allele frequency for said variant in the tumor sample;

c) acquiring values, as a function of SCI and SAFI, for:
a genomic segment total copy number (C) for each of a plurality of genomic segments;
a genomic segment minor allele copy number (M) for each of the plurality of genomic segments; and
sample purity (p),

wherein SCI, SAFI, C, M, and p are related to one another by the following:

r
ij

∼

N
(

log
2

⁢

p
*

C
i

+

(

1
-
p

)

*
2

p
*

(

∑
i

⁢

l
i

⁢

c
i

)

/

∑
i

⁢

l
i

+

(

1
-
p

)

*
2

,

σ
ri

,

and
⁢

⁢
fik

∼

N
⁡

(

p
*
Mi

+

(

1
-
p

)

*
1

p
*
Ci

+

(

1
-
p

)

*
2

,

σ
⁢

⁢
fi

)

,

when SCI and SAFI are notated as r ij and f ik , respectively; and
where r ij is the log ratio (LR) of subgenomic interval j within a genomic segment (S i ), C i is the total copy number (C) of S i , l i is the length of S i , fik is the minor allele frequency of SNP k within S i , M i is the copy number of a minor allele (M) at S i , and σ ri and σ fi are noise parameters; and
d) acquiring a value for mutation type, g, for which is indicative of the variant, being somatic, a subclonal somatic variant, germline, or not-distinguishable, wherein g, VAFI, p, C, and M are related to one another by the following:

VAFI
=

pM
+

g
⁡

(

1

Assignees

• Sun James Xin
• Yelensky Roman
• Found Medicine Inc

Inventors

• Sun James Xin
• Yelensky Roman

Classifications

• G16B20/00 Primary

  ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations · CPC title

• G06F19/18 Primary

  Physics · mapped topic

• G16B20/20 Primary

  Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection · CPC title

• G16B20/10

  Ploidy or copy number detection · CPC title