chr16-23635054-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024675.4(PALB2):​c.1492G>T​(p.Asp498Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,614,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: -0.262
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004059702).
BP6
Variant 16-23635054-C-A is Benign according to our data. Variant chr16-23635054-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182790.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=5, Likely_benign=5}. Variant chr16-23635054-C-A is described in Lovd as [Likely_benign]. Variant chr16-23635054-C-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000256 (39/152224) while in subpopulation EAS AF= 0.00676 (35/5174). AF 95% confidence interval is 0.005. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.1492G>T p.Asp498Tyr missense_variant Exon 4 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.1492G>T p.Asp498Tyr missense_variant Exon 4 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00675
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000477
AC:
120
AN:
251452
Hom.:
0
AF XY:
0.000552
AC XY:
75
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00587
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000139
AC:
203
AN:
1461880
Hom.:
2
Cov.:
33
AF XY:
0.000155
AC XY:
113
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00378
Gnomad4 SAS exome
AF:
0.000394
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00676
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000278
Hom.:
0
Bravo
AF:
0.000261
ExAC
AF:
0.000511
AC:
62
Asia WGS
AF:
0.00202
AC:
7
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4
Dec 30, 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. -

May 18, 2021
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 22, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
May 13, 2019
Leiden Open Variation Database
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: curation

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

Jun 16, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26411315, 28580595, 23977390, 25186627, 26283626, 26692951, 23555315, 27783279, 28796317, 28825143, 30309218, 28767289, 29338689, 31757951) -

Mar 20, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: 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

- -

not specified Benign:2
Jan 09, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PALB2 c.1492G>T (p.Asp498Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251452 control chromosomes, predominantly at a frequency of 0.0059 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 38 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 East Asian origin. c.1492G>T has been reported in the literature as a non-specific variant in individuals affected with a variety of cancers (example, Nakagomi_2015, Phuah_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (APC c.3184_3187delCAAA, p.Gln1062ValfsX63), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of likely benign (n=6)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1
May 01, 2019
Cancer Genomics Group, Japanese Foundation For Cancer Research
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Fanconi anemia complementation group N Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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.Asp498Tyr variant was identified in 133 of 21516 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer and was present in 397 of 51832 control chromosomes (frequency: 0.008) from healthy individuals (Momozawa 2018, Phuah 2013, Rashid 2018, Tung 2015). The variant was also identified in dbSNP (ID: rs75023630) as "With Uncertain significance, other allele", ClinVar (classified as benign by Invitae and Ambry Genetics; as likely benign by four submitters; as uncertain significance by two submitters), and LOVD 3.0 (6x as benign or likely benign). The variant was identified in control databases in 131 of 277200 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6462 chromosomes (freq: 0.0002), East Asian in 118 of 18868 chromosomes (freq: 0.006), and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, and Finnish, populations. The p.Asp498 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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
0.11
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.026
T;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.0041
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
.;L
PrimateAI
Benign
0.26
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Benign
0.088
Sift
Uncertain
0.018
D;D
Sift4G
Uncertain
0.033
D;D
Polyphen
0.90
.;P
Vest4
0.36
MVP
0.49
MPC
0.34
ClinPred
0.13
T
GERP RS
-0.22
Varity_R
0.087
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs75023630; hg19: chr16-23646375; API