NM_024675.4:c.1010T>C

Variant names:

• chr16-23635536-A-G
• rs45494092
• NM_024675.4:c.1010T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024675.4(PALB2):​c.1010T>C​(p.Leu337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,613,480 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.015 (37 hom., cov: 32)
  • Exomes 𝑓: 0.019 (285 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:27 O:1
• Conservation: PhyloP100: 0.842

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021042824).
• BP6: Variant 16-23635536-A-G is Benign according to our data. Variant chr16-23635536-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126582.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=15, Likely_benign=2, not_provided=1}. Variant chr16-23635536-A-G is described in Lovd as [Benign]. Variant chr16-23635536-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2216/152220) while in subpopulation NFE AF= 0.0211 (1437/68006). AF 95% confidence interval is 0.0202. There are 37 homozygotes in gnomad4. There are 1102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1010T>C	p.Leu337Ser	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1010T>C	p.Leu337Ser	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2215 AN: 152102 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0147 AC: 3679 AN: 250924 Hom.: 45 AF XY: 0.0143 AC XY: 1937 AN XY: 135676

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00658

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00373

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0191 AC: 27915 AN: 1461260 Hom.: 285 Cov.: 32 AF XY: 0.0186 AC XY: 13508 AN XY: 726942

Gnomad4 AFR exome AF: 0.00276

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00354

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0146 AC: 2216 AN: 152220 Hom.: 37 Cov.: 32 AF XY: 0.0148 AC XY: 1102 AN XY: 74438

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0399

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0163 Hom.: 44

Bravo AF: 0.0110

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0142 AC: 1729

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:27 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7 Other:1

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 11, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Benign:7

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 23, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 03, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:6

Aug 07, 2019

Leiden Open Variation Database

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP4, BS1, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1 Benign:4

May 10, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Mar 23, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Breast and/or ovarian cancer Benign:1

Jan 14, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Leu337Ser variant was identified in 190 of 11072 proband chromosomes (frequency: 0.0175) from individuals or families with CMM, breast, ovarian cancer, and was present in 98 of 6466 control chromosomes (frequency: 0.015) from healthy individuals (Aoude 2014, Catucci 2014, Garcia 2009, Nguyen-Dumont 2013, Tischkowitz 2012, Teo 2013, Prokofyeva 2012, Wong-Brown 2014, Zheng 2012). The variant was also identified in dbSNP (ID: rs45494092) as “With other allele,” ClinVar (classified as benign by Ambry Genetics, Vantari Genetics, Color Genomics, DGDCHP, PreventionGenetics, Counsyl, Invitae, GeneDx, Pathway Genomics; classified as likely benign by Illumina; classified as uncertain significance by CGLPMCC, PALB2 database), Clinvitae (classified with conflicting interpretations of pathogenicity by ClinVar), LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 42189 (43 homozygous) of 276766 chromosomes at a frequency of 0.01524 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu337 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.041
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.018	D;T
Polyphen		0.29	.;B
Vest4		0.065
MPC		0.077
ClinPred		0.0078	T
GERP RS		2.6
Varity_R		0.074
gMVP		0.25

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

Other links and lift over

dbSNP: rs45494092; hg19: chr16-23646857; COSMIC: COSV55167558; COSMIC: COSV55167558;