NM_024675.3(PALB2):c.3508C>T (p.His1170Tyr) AND Familial cancer of breast

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000226949.4

Allele description

NM_024675.3(PALB2):c.3508C>T (p.His1170Tyr)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.3(PALB2):c.3508C>T (p.His1170Tyr)

Other names:

p.H1170Y:CAT>TAT

HGVS:

NC_000016.10:g.23603512G>A
NG_007406.1:g.42846C>T
NM_024675.3:c.3508C>T
NP_078951.2:p.His1170Tyr
LRG_308t1:c.3508C>T
LRG_308:g.42846C>T
LRG_308p1:p.His1170Tyr
NC_000016.9:g.23614833G>A
Q86YC2:p.His1170Tyr
p.H1170Y

Protein change:

H1170Y

Links:

UniProtKB: Q86YC2#VAR_066384; dbSNP: rs200283306

NCBI 1000 Genomes Browser:

rs200283306

Allele Frequency:

0.00007(A)

Molecular consequence:

NM_024675.3:c.3508C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: CHEK2-Related Breast Cancer
Identifiers:: MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000290880	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Uncertain significance (Jan 4, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24448499, 26689913, 21618343, 28591191, 26315354, 28492532
SCV000487879	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 24, 2015)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24448499, 23555315, 26206375, 26315354, 21618343 Counsyl Autosomal Dominant Disease Classification criteria (2015) Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000290880

Invitae

criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))

Uncertain significance
(Jan 4, 2018)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000487879

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 24, 2015)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015)

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]

PMID:: 26689913
PMCID:: PMC4703835

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability.

Stafford JL, Dyson G, Levin NK, Chaudhry S, Rosati R, Kalpage H, Wernette C, Petrucelli N, Simon MS, Tainsky MA.

PLoS One. 2017;12(6):e0178450. doi: 10.1371/journal.pone.0178450.

PubMed [citation]

PMID:: 28591191
PMCID:: PMC5462348

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000290880.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces histidine with tyrosine at codon 1170 of the PALB2 protein (p.His1170Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs200283306, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ovarian cancer, as well as in unaffected control individuals (PMID: 21618343, 24448499, 26315354, 26689913, 28591191). ClinVar contain an entry for this variant (Variation ID: 141320). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000487879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 12, 2018

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