16-23635504-G-T

Position:

chr16-23635504-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_024675.4(PALB2):c.1042C>A(p.Gln348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q348Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 0.401

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_024675.4

BP4

Computational evidence support a benign effect (MetaRNN=0.05169323).

BP6

Variant 16-23635504-G-T is Benign according to our data. Variant chr16-23635504-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141588.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=7, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1042C>A	p.Gln348Lys	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1042C>A	p.Gln348Lys	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152174

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251120

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign:1

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 05, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 348 of the PALB2 protein (p.Gln348Lys). This variant is present in population databases (rs375699023, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141588). 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 16, 2020	Variant summary: PALB2 c.1042C>A (p.Gln348Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 257982 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.3e-05 vs 0.00016), allowing no conclusion about variant significance. c.1042C>A has been reported in the literature in at least one individual affected with breast cancer (Decker_2017), but also in healthy controls (Ramus_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant associated with Hereditary Breast and Ovarian Cancer has been reported in an internal sample (BRCA2 c.9789_9790delGA , p.Asn3264LeufsX12), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as likely benign (n=1) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2021	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.1042C>A, in exon 4 that results in an amino acid change, p.Gln348Lys. This sequence change has been described in gnomAD with a frequency of 0.0085% in the Non-Finnish European sub-population (dbSNP rs375699023). The p.Gln348Lys change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. The p.Gln348Lys substitution appears to be tolerated using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with PALB2-related. Due to the lack of sufficient evidences, the clinical significance of the p.Gln348Lys change remains unknown at this time. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2022	The p.Q348K variant (also known as c.1042C>A), located in coding exon 4 of the PALB2 gene, results from a C to A substitution at nucleotide position 1042. The glutamine at codon 348 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2016	- -

Chordoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Integrative Tumor Epidemiology Branch, National Institutes of Health

Mar 22, 2021

Modestly reduce HRR activity -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2024

Published functional studies suggest no damaging effect: homologous recombination repair similar to wildtype and normal co-localization in the nucleus with BRCA1 (PMID: 35762214); In silico analysis supports that this missense variant does not alter protein structure/function; Observed to segregate in a single family with multiple individuals with chordoma or juvenile pilocytic astrocytoma, but was also present in unaffected individuals (PMID: 35762214); Identified in an individual with breast cancer (PMID: 28779002); This variant is associated with the following publications: (PMID: 26315354, 36387127, 35762214, 28779002) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

N;N

Sift

Benign

0.38

T;T

Sift4G

Benign

0.81

T;T

Polyphen

0.18

.;B

Vest4

0.16

MVP

0.43

MPC

0.066

ClinPred

0.043

GERP RS

3.8

Varity_R

0.089

gMVP

0.28

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