rs180177125

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024675.4(PALB2):c.2773G>C(p.Val925Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,607,262 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V925M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 0.0900

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11346647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2773G>C	p.Val925Leu	missense_variant	8/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2773G>C	p.Val925Leu	missense_variant	8/13	1	NM_024675.4	P1
	ENST00000561764.1 linkuse as main transcript	n.590C>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250490

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135624

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:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1455124

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

724318

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:

0.0000398

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 925 of the PALB2 protein (p.Val925Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). 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	MGZ Medical Genetics Center	Apr 11, 2022	- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Sep 30, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 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; Observed in individuals with breast, ovarian, prostate, or colon cancer (Tischkowitz et al., 2008; Papi et al., 2010; Maxwell et al., 2016; DeRycke et al., 2017; Myszka et al., 2017); This variant is associated with the following publications: (PMID: 18288683, 19763884, 26635394, 29052111, 27153395, 24485656, 19609323, 20871615, 17420451, 28944238) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2023	The p.V925L variant (also known as c.2773G>C), located in coding exon 8 of the PALB2 gene, results from a G to C substitution at nucleotide position 2773. The valine at codon 925 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual from a cohort of 95 prostate cancer families and thought unlikely to be pathogenic by authors (Tischkowitz M et al. Prostate. 2008 May;68(6):675-8). This variant was also identified in a patient with colorectal cancer who met Amsterdam criteria whose tumor was mismatch repair proficient (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Another study detected this alteration in 1/338 breast cancer patients and 0/89 ovarian cancer patients from Poland and Ukraine (Myszka A et al. Fam. Cancer. 2018 07;17:345-349). This amino acid position is not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 05, 2023	This missense variant replaces valine with leucine at codon 925 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 individuals affected with breast and prostate cancer in the literature (PMID: 18288683, 19763884, 29052111, 29522266) and in a breast cancer case-control meta-analysis in 6/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010124). This variant has been identified in 4/245296 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. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.61

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.75

N;N

Sift

Benign

0.37

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.23

.;B

Vest4

0.20

MutPred

0.36

.;Gain of sheet (P = 0.0344);

MVP

0.56

MPC

0.054

ClinPred

0.10

GERP RS

2.7

Varity_R

0.078

gMVP

0.40

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