rs61756147

Variant names:

• chr16-23636248-G-A
• rs61756147
• NM_024675.4:c.298C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23636248-G-A
• chr16-23636248-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_024675.4(PALB2):​c.298C>T​(p.Leu100Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,770 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. L100V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:8 O:2
• Conservation: PhyloP100: 0.0960
• Publications: 18 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020982713).
• BP6: Variant 16-23636248-G-A is Benign according to our data. Variant chr16-23636248-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126698.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.298C>T	p.Leu100Phe	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.298C>T	p.Leu100Phe	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251306 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000359 AC: 525 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.000351 AC XY: 255 AN XY: 727154

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000437 AC: 486 AN: 1111906

Other (OTH) AF: 0.000546 AC: 33 AN: 60390

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000379 AC: 4 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000277 Hom.: 1

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:5

May 08, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 18, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2022

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 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. -

not provided Uncertain:3 Other:1

Oct 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found to have a statistically significant association with breast cancer risk in a multi-ethnic exome array study (Haiman et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 25479140, 26283626, 21409391, 26315354, 25225577, 25186627, 26976419, 27060149, 26689913, 28767289, 28779002, 32659497, 32546565, 28259476, 35263119, 30541756, 28873162, 32885271, 33471991, 20871615, 19369211, 23555315, 34326862) -

May 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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

Apr 17, 2023

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, 0.00033 (42/129102 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 25225577 (2014), 26315354 (2015), 26976419 (2016), 28767289 (2017), and 28873162 (2017)). This variant has also been identified in healthy, unaffected individuals (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 26283626 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: flagged submission

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Familial cancer of breast Uncertain:2 Benign:2

Jan 10, 2025

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]. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

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

- -

PALB2-related disorder Uncertain:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.298C>T variant is predicted to result in the amino acid substitution p.Leu100Phe. This variant has been detected in patients with breast and ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hartley et al. 2014. PubMed ID: 25225577, Table S4; Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4; Kanchi et al. 2014. PubMed ID: 24448499, sup data 8) and pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289, referred to as c.298G>A; Grant et al. 2015. PubMed ID: 25479140, Sup. Table 1). However, it was detected in an equal number of cases and controls (2) in one of these studies (Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4). This variant is documented in the gnomAD general population database with a minor allele frequency of ~0.03% among non-Finnish Europeans and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126698/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Pancreatic cancer, susceptibility to, 3 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.Leu100Phe variant was identified in 5 of 11930 proband chromosomes (frequency: 0.0004) from American, Canadian and Australian individuals or families with BRCA1/2 negative breast cancer, familial breast or breast/ovarian cancer, or ovarian cancer and was present in 4 of 10858 control chromosomes (frequency: 0.0003) from healthy individuals (Ramus_2015_26315354, Thompson_2015_26283626, Tung_2016_26976419, Wong_2011_21409391, Hartley_2014_25225577). The variant was identified in the following databases: dbSNP (ID: rs61756147) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae, Ambry Genetics, Cancer Genetics Laboratory (Peter MacCallum Cancer Center) and the PALB2 database), Clinvitae (3x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x), and in control databases in 46 of 277092 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Observation by population include “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34398 chromosomes (freq: 0.00003), European Non-Finnish in 42 of 126642 chromosomes (freq: 0.0003), and European Finnish in 2 of 25786 chromosomes (freq: 0.00008); it was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The variant was not identified in Cosmic or MutDB. The p.Leu100 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Phe impacts the protein; however, 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. This variant is classified as a variant of uncertain significance. -

Fanconi anemia complementation group N Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer Uncertain:1

Dec 21, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 09, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PALB2 c.298C>T (p.Leu100Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 293556 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, this variant has been also reported in 3/7325 European American women who were older than age 70 years and cancer free (in the FLOSSIES database). c.298C>T has been reported in the literature in individuals affected with different types of cancer (Wong 2011, Haiman 2013, Hartley 2014, Tung 2014, Grant 2015, Ramus 2015, Lu 2015, Shindo 2017, Seligson_2019), but was also found in healthy controls (Thompson 2015, 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 has been reported (BRCA1 c.5266dupC (p.Gln1756Profs*74), Tung 2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as VUS (n=6), Likely Benign (n=5) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome;C1835817:Fanconi anemia complementation group N Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 09-21-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.096
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.014
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.0080	B
Vest4		0.083
MVP		0.15
MPC		0.058
ClinPred		0.051	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.048
Mutation Taster		=97/3	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: rs61756147; hg19: chr16-23647569; COSMIC: COSV55162751;