16-23629716-A-G

Position:

chr16-23629716-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024675.4(PALB2):c.2438T>C(p.Ile813Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: -1.14

Variant links:

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 links:

PALB2 (HGNC:):

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022354811).

BP6

Variant 16-23629716-A-G is Benign according to our data. Variant chr16-23629716-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2438T>C	p.Ile813Thr	missense_variant	5/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2438T>C	p.Ile813Thr	missense_variant	5/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 27, 2017	The PALB2 c.2438T>C;p.Ile813Thr variant has not been described in the medical literature or in gene-specific databases. The variant is listed in the ClinVar database (Variation ID: 410141) and the dbSNP variant database (rs763191051) with an allele frequency of 0.001624 percent (4/246270 alleles) in the Genome Aggregation Database. The isoleucine residue at this position is only partially conserved across species; amongst other mammalian species, 21 have isoleucine, 19 have threonine and 19 have another amino acid at this position. Furthermore, computational algorithms (AlignGVGD, SIFT, MutationTaster) all predict this variant is tolerated. Additionally, missense variants in PALB2 are not a known pathogenic mechanism for cancer predisposition (Tavtigian 2014, Tischkowitz 2012). Considering available information, this variant is classified as likely benign. References: Tavtigian SV and Chenevix-Trench G. Growing recognition of the role for rare missense substitutions in breast cancer susceptibility. Biomark Med. 2014;8(4):589-603. Tischkowitz M et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat. 2012 Apr;33(4):674-80. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18446436, 24485656, 28779002, 35264596) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2017	Variant summary: The PALB2 c.2438T>C (p.Ile813Thr) variant located in the WD40/YVTN repeat-like-containing domain (via InterPro) involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 4/246270 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). A publication cites the variant in two affected individuals, however, limited information is provided (ie, co-occurrence and/or cosegregation data). A clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 813 of the PALB2 protein (p.Ile813Thr). This variant is present in population databases (rs763191051, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 18446436, 35264596). ClinVar contains an entry for this variant (Variation ID: 410141). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 22, 2024	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2022	This missense variant replaces isoleucine with threonine at codon 813 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals or families affected with breast and/or ovarian cancer and it also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010897). This variant has been identified in 4/251486 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

The PALB2 c.2438T>C variant is predicted to result in the amino acid substitution p.Ile813Thr. This variant has been reported in individuals with a personal or family history of breast cancer (Cao et al. 2008. PubMed ID: 18446436; Table S3, Guindalini et al 2022. PubMed ID: 35264596). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410141/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0080

DANN

Benign

0.33

DEOGEN2

Benign

0.0049

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

.;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.032

Sift

Benign

1.0

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

.;B

Vest4

0.054

MutPred

0.096

.;Gain of glycosylation at I813 (P = 0.0054);

MVP

0.17

MPC

0.062

ClinPred

0.034

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.062

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over