16-23635504-G-T

Variant names:

• chr16-23635504-G-T
• rs375699023
• NM_024675.4:c.1042C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q348E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 0.401
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -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 4 benign, 30 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 VariationId is 141588.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.1042C>A	p.Gln348Lys	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.982C>A	p.Gln328Lys	missense	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.1042C>A	p.Gln348Lys	missense	Exon 4 of 12	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.1042C>A	p.Gln348Lys	missense	Exon 4 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.157C>A	p.Gln53Lys	missense	Exon 4 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.1048C>A	p.Gln350Lys	missense	Exon 4 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152174 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251120 AF XY: 0.0000663

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461558 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:4 Benign:1

Sep 05, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 12, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 07, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense change has been observed in individual(s) with breast cancer (PMID: 37937776). ClinVar contains an entry for this variant (Variation ID: 141588). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Jul 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 07, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:2

Aug 08, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.1042C>A variant is predicted to result in the amino acid substitution p.Gln348Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141588/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Chordoma Uncertain:1

Mar 22, 2021

Integrative Tumor Epidemiology Branch, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Modestly reduce HRR activity

not provided Uncertain:1

Aug 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 suggests 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, 37937776)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.020
Sift	Benign	0.38	T
Sift4G	Benign	0.81	T
Polyphen		0.18	B
Vest4		0.16
MVP		0.43
MPC		0.066
ClinPred		0.043	T
GERP RS		3.8
Varity_R		0.089
gMVP		0.28
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs375699023; hg19: chr16-23646825;