16-23614059-A-G

Variant names:

• chr16-23614059-A-G
• rs138273800
• NM_024675.4:c.3146T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_024675.4(PALB2):​c.3146T>C​(p.Met1049Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M1049I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16 B:2
• Conservation: PhyloP100: 5.72
• Publications: 5 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

ENSG00000261723 (HGNC:58305):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.3146T>C	p.Met1049Thr	missense	Exon 11 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3086T>C	p.Met1029Thr	missense	Exon 10 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3074T>C	p.Met1025Thr	missense	Exon 10 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.3146T>C	p.Met1049Thr	missense	Exon 11 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.2261T>C	p.Met754Thr	missense	Exon 11 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.3152T>C	p.Met1051Thr	missense	Exon 11 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251228 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461210 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111516

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:5 Benign:1

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely 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].

Feb 24, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1049 of the PALB2 protein (p.Met1049Thr). This variant is present in population databases (rs138273800, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354, 26580448). ClinVar contains an entry for this variant (Variation ID: 141785). 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 expected to disrupt PALB2 protein function with a positive 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.

Mar 14, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 17, 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.

not specified Uncertain:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 06, 2019

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.3146T>C (p.Met1049Thr) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3146T>C has been reported in the literature in individuals affected with Breast Cancer and Epithelial Ovarian cancer (Thompson_2015, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary forms of Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

not provided Uncertain:2

Sep 30, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of osteosarcoma, breast, or ovarian cancer (PMID: 26283626, 26580448, 26315354); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26580448, 26283626, 26315354, 24485656, 19609323, 20871615, 33471991, 25085752, 36627197)

May 24, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 14, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with threonine at codon 1049 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with breast cancer (PMID: 26283626), ovarian cancer (PMID: 26315354) and osteosarcoma (PMID: 26580448), respectively. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010778). This variant has been identified in 6/282634 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.

Aug 08, 2022

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

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.3146T>C variant is predicted to result in the amino acid substitution p.Met1049Thr. This variant has been reported in individuals with osteosarcoma, breast, or ovarian cancer (Table S4, Ramus et al. 2015. PubMed ID: 26315354; Table 3, Thompson et al. 2015. PubMed ID: 26283626; Table S4a, Zang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141785/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1

May 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group N Uncertain:1

Oct 25, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.3146T>C (p.Met1049Thr) missense change has a maximum subpopulation frequency of 0.0056% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 26283626, 32885271) and ovarian cancer (PMID: 26315354). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1

Nov 13, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1049 of the PALB2 protein (p.Met1049Thr).This amino acid position is conservative (PhyloP=5.26). This variant is present in population databases (rs138273800, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354, 26580448,19609323, 24485656, 20871615). ClinVar contains an entry for this variant (Variation ID: 141785). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. 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.

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 p.Met1049Thr variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs138273800) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, GeneDx), Clinvitae (classified as uncertain significance by ClinVar, Invitae), MutDB, databases. The variant was identified in control databases in 5 of 277046 chromosomes at a frequency of 0.000018 (Genome Aggregation Consortium Feb 27, 2017). Although the p.Met1049 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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. The variant is located within the ‘WD40-repeat-containing domain’ functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		0.91	P
Vest4		0.84
MVP		0.73
MPC		0.36
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.57
gMVP		0.46
Mutation Taster		=40/60	disease causing

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: rs138273800; hg19: chr16-23625380;