rs200875161

Positions:

chr16-23630127-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BA1BP1

This summary comes from the ClinGen Evidence Repository: The c.2027T>C variant in PALB2 is a missense variant predicted to cause a substitution of isoleucine by threonine at amino acid 676 (p.Ile676Thr). This variant has been observed in the homozygous state in multiple individuals without Fanconi Anemia (Ambry Genetics). This variant has a gnomAD v.2.1.1 filtering allele frequency of 0.005 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in a protein assay (PMID 33964450); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BS2, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294362/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: 0.414

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2027T>C	p.Ile676Thr	missense_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2027T>C	p.Ile676Thr	missense_variant	5/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000803

AC:

202

AN:

251436

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00581

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000118

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000351

ExAC

AF:

0.000700

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	This variant is associated with the following publications: (PMID: 23555315, 25980754, 26315354) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2016	Variant summary: The PALB2 c.2027T>C (p.Ile676Thr) variant causes a missense change involving a non-conserved nucleotide with 4/5 in silico tools predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 85/128258 (1/1428), predominantly in the Latino cohort, 85/11578 (1/136), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PALB2 variant of 1/6397. Therefore, suggesting the variant is a common polymorphism found in population(s) of Latino origin. The variant of interest has been reported in affected individuals via publications. Clinical diagnostic laboratories have cited the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2021	- -

Familial cancer of breast

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.2027T>C variant in PALB2 is a missense variant predicted to cause a substitution of isoleucine by threonine at amino acid 676 (p.Ile676Thr). This variant has been observed in the homozygous state in multiple individuals without Fanconi Anemia (Ambry Genetics). This variant has a gnomAD v.2.1.1 filtering allele frequency of 0.005 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in a protein assay (PMID 33964450); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BS2, BP1) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

DANN

Benign

0.64

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.97

N;N

REVEL

Benign

0.0030

Sift

Benign

0.21

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0050

.;B

Vest4

0.076

MVP

0.22

MPC

0.063

ClinPred

0.0082

GERP RS

-1.1

Varity_R

0.022

gMVP

0.085

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