rs61756146

Variant names:

• chr16-23622987-G-A
• rs61756146
• NM_024675.4:c.2978C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23622987-G-A
• chr16-23622987-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_024675.4(PALB2):​c.2978C>T​(p.Thr993Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T993A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 1.48
• Publications: 8 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29418924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2978C>T	p.Thr993Met	missense_variant	Exon 9 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2978C>T	p.Thr993Met	missense_variant	Exon 9 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251460 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Apr 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a slight decrease in homologous recombination efficiency (Ng 2021); Observed in individuals with breast cancer or cervical rhabdomyosarcoma (Cowan 2018, Ng 2021); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 33811135, 30014022) -

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00002 (5/251460 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has reported in individuals with breast cancer (PMID: 33811135 (2022), 33471991 (2021)) as well as in unaffected healthy individuals ((PMID: 33811135 (2022), 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast Uncertain:2 Benign:1

Aug 18, 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]. -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 993 of the PALB2 protein (p.Thr993Met). This variant is present in population databases (rs61756146, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 33811135). ClinVar contains an entry for this variant (Variation ID: 232056). 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. -

Sep 01, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Oct 23, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1 c.2978C>T, located in exon 9 of the PALB2 gene, is predicted to result in the substitution of threonine by methionine at codon 993, p.(Thr993Met). The SpliceAI algorithm predicts no significant impact on splicing and there is a very low likelihood that missense variants are pathogenic in PALB2 (BP1). This variant is found in 4/268320 alleles at a frequency of 0.0015% in the gnomAD v2.1.1 database, non-cancer dataset. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. It has been reported in the ClinVar database (1x likely benign, 9x uncertain significance) and in the LOVD database (1x likely benign, 2x NA). Based on the currently available information, c.2978C>T is classified as an uncertain significance variant according to ClinGen-PALB2 Guidelines version v1.0.0. -

May 17, 2025

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. -

Jul 11, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 993 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 at least five individuals affected with breast cancer and one unaffected individual (PMID: 33471991, 33811135). This variant has been identified in 5/251460 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. -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1

Nov 06, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	.;M
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.092
Sift	Benign	0.083	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.99	.;D
Vest4		0.40
MutPred		0.31		.;Loss of sheet (P = 0.0228);
MVP		0.63
MPC		0.25
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.083
gMVP		0.40
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61756146; hg19: chr16-23634308; COSMIC: COSV108745886;